SOX11-Related Neurodevelopmental Disorder

Mendelian MONDO:0014376 Pathograph 17 Show in embeddings browser Neurodevelopmental disorder Autosomal dominant disease

SOX11-related neurodevelopmental disorder is a rare autosomal dominant condition caused by heterozygous de novo loss-of-function or missense variants in SOX11 (2p25.2), or by microdeletions encompassing the gene. SOX11 encodes a single-exon SoxC-group high-mobility-group (HMG) box transcription factor that drives neural progenitor proliferation, neuronal differentiation, and neuronal survival during fetal brain development. Core clinical features are neurodevelopmental delay and intellectual disability, microcephaly, hypotonia, short stature, autistic traits, and mild distal-limb findings (fifth-finger clinodactyly, hypoplastic fifth nails). A subset of individuals have ocular malformations (microphthalmia, iris coloboma) or hypogonadotropic hypogonadism, which is why OMIM/MONDO name the entity "intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism". The disorder is repeatedly labelled "Coffin-Siris syndrome 9" in the literature because the first two probands had a mild Coffin-Siris-like presentation, but SOX11 is a transcriptional effector acting DOWNSTREAM of the PAX6-BAF (SWI/SNF) complex rather than a BAF core subunit, and SOX11 cases carry a blood DNA methylation episignature that separates them from the BAFopathies.

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Classifications

Harrison's Chapter

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Mappings

MONDO

MONDO:0100626 SOX11-related complex neurodevelopmental disorder with or without congenital anomalies Not Yet Curated

MONDO:0100626 is the newer, ClinGen-grounded term for the same SOX11 entity and carries the same RO:0004003 relation to HGNC:11191 (SOX11). MONDO lists this entry's anchor label ("intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism") as a NARROW synonym of MONDO:0100626, hence skos:broadMatch. This entry is deliberately anchored on MONDO:0014376 (the OMIM:615866-xrefed term named in the curation request); MONDO:0100626 is the term a future re-anchoring should use.

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Inheritance

Autosomal dominant SOX11 haploinsufficiency HP:0000006

Heterozygous loss of SOX11 function (intragenic point variants or whole-gene 2p25.2 deletion) is sufficient to cause disease, indicating that the paralogous SoxC factors SOX4 and SOX12 cannot compensate for reduced SOX11 dosage in human neurodevelopment.

Autosomal dominant inheritance Expressivity: VARIABLE De novo rate: Most reported pathogenic SOX11 variants are de novo; in a systematic review of SOX11-related hypogonadotropic hypogonadism, 15 of 18 variants with parental testing were proven de novo. Rare transmission from a mildly affected parent has been documented.

Show evidence (2 references)

PMID:42168980 SUPPORT Human Clinical

"Thirty unique variants were identified, 17/30 clustering within the HMG domain and 15/18 proven de-novo."

Quantifies the predominance of de novo origin and the clustering of pathogenic variants in the HMG DNA-binding domain.

PMID:33785884 SUPPORT Human Clinical

"Maternal transmission of a mild Coffin-Siris syndrome phenotype caused by a SOX11 missense variant."

Documents that a pathogenic SOX11 missense variant can be inherited from a mildly affected mother, so de novo occurrence is usual but not obligatory.

Discussions and Knowledge Gaps

What is the true population frequency of each SOX11 phenotype, and in particular of hypogonadotropic hypogonadism and ocular malformation?

KNOWLEDGE GAP OPEN sox11_phenotype_frequency_gap

Attached to

pathophysiology#Impaired Hypothalamic-Pituitary Gonadotropic Axis Development pathophysiology#Disrupted Ocular Morphogenesis

The two qualifying features in the OMIM/MONDO disease name are ocular malformation and hypogonadotropic hypogonadism, both described as optional. The ocular half of that gap is now partly closed: a 2025 systematic ophthalmological review (PMID:40933692) pools 58 published single-nucleotide variant cases and reports ophthalmological malformation in 26/58 (44.83%), with ocular motor disorder the most prevalent subtype at 15/58 (29.31%). That pooled figure is what the Ophthalmological Malformation phenotype is banded on. It does not resolve the apraxia-specific rate, because "ocular motor disorder" is a broader category than Cogan-type oculomotor apraxia, and it does not address hypogonadotropic hypogonadism, for which no denominator-based frequency has been published in a source obtainable here. Elsewhere in the entry, bands are now derived preferentially from the pooled literature table in PMID:35938035 (Table 1, "Phenotypic comparison of our patient with reported patients", n = 58 reported patients) rather than from the 7-patient Sanchez-Martin series: intellectual disability 38/40 (95%, VERY_FREQUENT, upgraded from FREQUENT), developmental delay 36/37 (97%), microcephaly 11/28 (39%), short stature 10/30 (33%), fifth-finger clinodactyly 10/55 (18%, OCCASIONAL - corrected down from FREQUENT, which had been derived from the n=7 outlier figure of 5/7), and hypoplastic nails 6/55 (11%, OCCASIONAL - previously unbanded). Each pooled row has a phenotype-specific denominator smaller than 58 because the row reflects only those individuals in whom the feature was reported; cryptorchidism 5/6 is left unbanded for that reason, since 6 is the reporting-conditional subset of 28 reported males. Two denominators remain out of reach: the 38-patient Al-Jawahiri cohort (PMID:35341651) reports per-phenotype counts only in body text, and a re-fetch on 2026-07-31 still returned an abstract-only cache despite the paper carrying PMCID PMC9245088, so its hypogonadotropic hypogonadism (8/38) and abnormal brain MRI (12/20) figures are not asserted here. Bands continue to be omitted rather than guessed wherever no denominator is quotable from a cached source.

Proposed experiments

Denominator-based multisystem phenotyping of the full SOX11 cohort

sox11_denominator_phenotyping

Systematic phenotyping of the full published and registry SOX11 cohort with mandatory endocrine and ophthalmological evaluation of every participant, so that the "with or without" qualifiers in the disease name can be replaced with real frequencies rather than ascertainment-biased case counts.

Decision criterion

Per-phenotype frequencies with explicit denominators for hypogonadotropic hypogonadism and ocular malformation across an unselected SOX11 cohort.

Do the homozygous-null and morpholino knockdown models used for SOX11 faithfully represent the human heterozygous loss-of-function state?

HUMAN MODEL MISMATCH OPEN sox11_dosage_model_mismatch

Attached to

pathophysiology#Reduced Cortical Neurogenesis and Brain Growth pathophysiology#Impaired Cochlear Nerve Development pathophysiology#Disrupted Nephrogenic Gdnf Domain Restriction pathophysiology#Mandibular Hypoplasia with Secondary Palatal Shelf Obstruction

Much of the mechanistic evidence for the microcephaly and cochlear-nerve arms comes from homozygous Sox11-null mice, zebrafish sox11a/b double morphants, and Xenopus morphants - all effectively complete loss of function - whereas human disease is heterozygous. Tsurusaki et al. note that physical and functional abnormalities in heterozygous mice have not been described. The dosage mismatch is partly mitigated by the isogenic SOX11+/- human embryonic stem cell model (PMID:31035284), which is the strongest dosage-matched evidence available, but that model is in vitro. The same zygosity caveat applies to the organ arms added from the deep research: the duplex-kidney and secondary-cleft-palate mechanisms come from Sox11 whole-gene-deletion mice, and the corresponding human findings in heterozygotes are milder (small or malrotated kidney; cleft palate in a single reported individual). The C. elegans model is explicit that the orthologous Y116C change is recessive, which is itself a dosage mismatch with the dominant human disease even though it supports the loss-of-function interpretation.

Proposed experiments

Deep phenotyping of Sox11 heterozygous mice

sox11_het_mouse_deep_phenotyping

Characterise head size, cortical neuron number, and auditory brainstem response in Sox11 heterozygous mice, the dosage-matched in vivo model that has not previously been assessed.

Decision criterion

Reduced brain size, reduced cortical neuron number, or elevated ABR thresholds in heterozygotes relative to littermate controls would confirm that single-copy loss is sufficient in vivo.

Isogenic SOX11+/- human cerebral organoids

sox11_het_organoid

Extend the existing two-dimensional isogenic SOX11+/- human embryonic stem cell model to three-dimensional cerebral organoids to test whether heterozygous dosage alone reduces neuron output in a human cortical context that includes outer radial glia.

Decision criterion

Reduced organoid size and cortical neuron output in SOX11+/- versus isogenic wild-type organoids.

Show evidence (1 reference)

PMID:24886874 SUPPORT Model Organism

"Physical and functional abnormalities in hetero- zygotes have not been described."

States directly that the heterozygous mouse - the dosage-matched model - has not been characterised, which is the substance of the mismatch.

What is the adult natural history of SOX11-related neurodevelopmental disorder, and do non-coding regulatory variants at the SOX11 locus cause it?

KNOWLEDGE GAP OPEN sox11_noncoding_and_natural_history_gap

Attached to

pathophysiology#Heterozygous SOX11 Loss of Function

Two distinct gaps sit on the same node. First, every reported pathogenic lesion to date is coding or whole-gene: no non-coding or regulatory SOX11 variant has been reported, despite a documented enhancer landscape at the locus, so the mutational spectrum in this entry may be incomplete by ascertainment rather than by biology. Second, the published cohort is paediatric-dominated; there is no natural-history study, no disease-specific quality-of-life instrument, no prognostic biomarker, and no clinical trial for this disorder, so the progression and outcome sections of this entry are intentionally empty rather than inferred.

Proposed experiments

Targeted regulatory-region sequencing at the SOX11 locus

sox11_regulatory_region_sequencing

Sequence the SOX11 promoter and annotated enhancer landscape in coding-negative individuals with a SOX11-syndrome-like phenotype or a SOX11 episignature, to test whether non-coding lesions account for unexplained cases.

Decision criterion

Identification of a non-coding variant that segregates with phenotype and reduces SOX11 expression in a reporter assay.

Prospective adult natural-history study

sox11_adult_natural_history

Longitudinal follow-up of a molecularly confirmed SOX11 cohort into adulthood with standardised endocrine, ophthalmological, audiological, skeletal, and adaptive-function outcome measures.

Decision criterion

Age-stratified outcome data sufficient to populate progression and prognosis for the entry.

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Pathophysiology

Heterozygous SOX11 Loss of Function

De novo missense variants clustering in the high-mobility-group (HMG) DNA-binding domain, truncating variants, or 2p25.2 microdeletions remove one functional copy of the single-exon SOX11 gene. Missense changes in the HMG domain either destabilise domain folding or distort the DNA-recognition loops.

SOX11 hgnc:11191

sequence-specific DNA binding by the HMG box GO:0043565 ↓ DECREASED

Downstream

Reduced Functional SOX11 Protein Dosage Deletion removes one copy outright; truncating variants remove the C-terminal transactivation domain; HMG-domain missense variants leave a nuclear-localised but DNA-binding-incompetent protein.

Show evidence (4 references)

PMID:24886874 SUPPORT Human Clinical

"Here we perform whole-exome sequencing in additional CSS patients, identifying de novo SOX11 mutations in two patients with a mild CSS phenotype."

First identification of de novo SOX11 variants as a cause of this neurodevelopmental phenotype.

PMID:24886874 SUPPORT Computational

"The two heterozygous mutations localize to the high-mobility group (HMG) domain."

Localises the causal missense changes to the DNA-binding domain; FoldX modelling in the same paper predicts destabilisation (S60P) or altered DNA-recognition-loop conformation (Y116C).

PMID:26543203 SUPPORT Human Clinical

"We identified seven individuals with chromosome 2p25 deletions involving SOX11. Trio exome sequencing identified three de novo SOX11 variants, two missense (p.K50N; p.P120H) and one nonsense (p.C29*)."

Establishes that whole-gene deletion and intragenic loss-of-function variants produce the same disorder, supporting haploinsufficiency.

+ 1 more reference

Reduced Functional SOX11 Protein Dosage

Roughly half the normal amount of functional SOX11 activity remains. This is a pure dosage lesion, not a dominant-negative one: disease missense proteins still localise correctly to the nucleus, and the recurrent Y116C change behaves as a recessive loss of function when modelled at the orthologous residue in Caenorhabditis elegans. Critically, the paralogous SoxC factors SOX4 and SOX12 do not compensate in humans. SOX11 protein abundance is also set post-translationally by USP11-mediated deubiquitination, an independent route to functional SOX11 insufficiency.

protein stabilization GO:0050821 ↓ DECREASED

DNA-binding transcription factor activity GO:0003700 ↓ DECREASED

Downstream

Impaired SOX11 Target Gene Transactivation Reduced functional SOX11 dosage lowers transactivation of SOX11 target genes at critical developmental windows.

Show evidence (4 references)

PMID:31035284 SUPPORT In Vitro

"demonstrating that in humans SOX11 haploinsufficiency cannot be compensated"

Establishes that the SoxC paralogues SOX4 and SOX12 do not buffer reduced SOX11 dosage in humans, which is why heterozygous loss is pathogenic.

PMID:40832700 SUPPORT Model Organism

"is a loss-of-function, recessive mutation that likely causes defects due to haploinsufficiency"

The recurrent SOX11 Y116C change, modelled at the orthologous SEM-2 Y160 residue, behaves as a recessive loss of function rather than a dominant-negative, supporting a pure dosage mechanism.

PMID:35938035 SUPPORT In Vitro

"WT and two missense mutant SOX11 protein localized in the nucleus"

Nuclear localisation is preserved for disease missense proteins, arguing against a trafficking defect or a sequestration/dominant-negative model and for a DNA-binding/transactivation dosage defect.

+ 1 more reference

Impaired SOX11 Target Gene Transactivation

SOX11 acts as a transcriptional activator at target promoters. Disease variants reduce SOX11-dependent transactivation in reporter assays, so the downstream neurodevelopmental gene programme is under-expressed at critical windows of brain development.

regulation of transcription by RNA polymerase II GO:0006357 ↓ DECREASED

DNA-binding transcription factor activity GO:0003700 ↓ DECREASED

Downstream

Neural Precursor Proliferation-Differentiation Imbalance Under-transactivation of neurogenic target genes shifts neural precursors away from timely neuronal differentiation.

Increased Neuronal Apoptosis Loss of SOX11-dependent survival signalling increases programmed death of newly generated neurons.

SOX11-Specific DNA Methylation Episignature Altered SOX11 transcriptional output is reflected in a reproducible genome-wide blood DNA methylation signature.

Elevated Hedgehog Signalling in the Developing Eye SOX11 normally restrains shha transcription; loss of that restraint raises Hedgehog pathway output during ocular morphogenesis.

Reduced FGF9-Driven Mandibular Mesenchyme Proliferation FGF9 is a direct SOX11 target driving proliferation in the developing mandible and palatal shelf.

Disrupted Nephrogenic Gdnf Domain Restriction SOX11 restricts the rostral extent of the Gdnf expression domain in the nephrogenic cord and regulates a protocadherin B cluster locus control region.

Impaired Hypothalamic-Pituitary Gonadotropic Axis Development Reduced SOX11 activity impairs development of the GnRH neuroendocrine axis and associated olfactory/pituitary structures.

Impaired Cochlear Nerve Development SOX11 is required for cochlear sensory neuron survival and axonal growth, so reduced activity can produce cochlear nerve deficiency.

Show evidence (3 references)

PMID:24886874 SUPPORT In Vitro

"Luciferase assays using the GDF5 promoter in HeLa and ATDC5 cells, showed both mutant proteins had decreased transcriptional activities compared with wild type"

Directly demonstrates that the disease-associated HMG-domain missense proteins are transcriptionally hypomorphic.

PMID:26543203 SUPPORT In Vitro

"Our luciferase reporter gene assays provide further evidence in support of this as they indicate a reduced ability of mutant SOX11 to induce gene expression."

Independent replication of reduced transactivation for a second set of patient variants.

PMID:32574812 SUPPORT Other

"SOX11 regulates progenitor and stem cell behavior, and often acts together with the other two SOXC group members, SOX4 and SOX12, in regulating developmental processes, including neurogenesis and skeletogenesis."

Review context for the developmental gene programme that SOX11 normally transactivates.

Neural Precursor Proliferation-Differentiation Imbalance

SOX11 haploinsufficiency shifts the balance between neural precursor proliferation and neuronal differentiation, so fewer neurons are generated per progenitor pool.

neural progenitor cell CL:0011020

neuron differentiation GO:0030182 ↓ DECREASED cell population proliferation GO:0008283 ↕ DYSREGULATED

Downstream

Reduced Cortical Neurogenesis and Brain Growth Fewer neurons are produced from the precursor pool, reducing cortical neuron output.

Show evidence (1 reference)

PMID:31035284 SUPPORT In Vitro

"SOX11 haploinsufficiency impaired the generation of neurons and resulted in a proliferation/differentiation imbalance of neural precursor cells and enhanced neuronal cell death."

Isogenic CRISPR/Cas9 SOX11+/- human embryonic stem cell model shows that one-copy loss alone is sufficient to produce this cellular phenotype.

Increased Neuronal Apoptosis

SOX11 also acts as a neuronal survival factor; reduced dosage increases apoptotic death of newly born neurons in the developing central nervous system.

neuron CL:0000540

positive regulation of neuron apoptotic process GO:0043525 ↑ INCREASED

Downstream

Reduced Cortical Neurogenesis and Brain Growth Loss of newly generated neurons compounds the reduced neuronal output and limits brain growth.

Show evidence (3 references)

PMID:31035284 SUPPORT In Vitro

"SOX11 haploinsufficiency impaired the generation of neurons and resulted in a proliferation/differentiation imbalance of neural precursor cells and enhanced neuronal cell death."

The same isogenic human stem cell model demonstrates enhanced neuronal death on loss of a single SOX11 copy.

PMID:24886874 SUPPORT Model Organism

"apoptotic increases exclusively in microcephalic embryos"

Acridine orange and TUNEL staining in sox11a/b zebrafish morphants link increased CNS apoptosis to the small-head phenotype.

PMID:26543203 SUPPORT Model Organism

"Sox11 knockdown does not alter proliferation but is associated with increased neuronal apoptosis"

Independent amphibian evidence that Sox11 loss acts predominantly through neuronal survival rather than proliferation in that context.

Reduced Cortical Neurogenesis and Brain Growth

The combination of impaired neuronal generation and increased neuronal death reduces the number of cortical neurons produced during fetal development, yielding a smaller brain with a thin cerebral cortex.

neurogenesis GO:0022008 ↓ DECREASED cerebral cortex development GO:0021987 ↓ DECREASED

cerebral cortex UBERON:0000956

Downstream

Microcephaly and Impaired Cognitive Development Reduced cortical neuron number manifests postnatally as microcephaly, developmental delay, and intellectual disability.

Show evidence (2 references)

PMID:26543203 SUPPORT Model Organism

"SOX11 null mice have reduced cortical neurogenesis secondary to reduced proliferation and abnormal differentiation of neuronal progenitor cells.3 This results in SOX11 null mice having reduced brain weights and thin cerebral cortices."

Mouse data establishing the tissue-level consequence of Sox11 loss on cortical neurogenesis and brain size.

PMID:26543203 SUPPORT Model Organism

"Morphants had significant reduction in head size compared with controls. This suggests that SOX11 loss of function can be associated with microcephaly."

Xenopus Sox11 knockdown reproduces reduced head size, linking the molecular lesion to the brain-growth phenotype.

Microcephaly and Impaired Cognitive Development

The clinical endpoint of the neural arm of the cascade: postnatal microcephaly with global developmental delay, intellectual disability, and a high burden of autistic traits.

Show evidence (2 references)

PMID:26543203 SUPPORT Human Clinical

"These individuals had microcephaly, developmental delay and shared dysmorphic features compatible with mild Coffin-Siris syndrome."

Human cohort observation of the microcephaly/developmental-delay endpoint in SOX11 deletion and point-variant carriers.

PMID:37558216 SUPPORT Human Clinical

"we made a confirmation that overall SOX11 abnormalities feature a distinctive disorder characterised by severe ID, high incidence of microcephaly and low frequency of congenital malformations"

Literature review of 32 well-characterised individuals confirming that severe intellectual disability plus microcephaly dominates the phenotype.

SOX11-Specific DNA Methylation Episignature

Individuals with pathogenic SOX11 variants carry a reproducible, disorder-specific genome-wide blood DNA methylation pattern. This episignature is mechanistically informative as well as diagnostically useful: it separates SOX11 syndrome from the BAF (SWI/SNF) chromatin remodeller disorders with which SOX11 is clinically lumped.

Show evidence (1 reference)

PMID:35341651 SUPPORT Human Clinical

"A distinctive pattern of blood DNA methylation was identified in SOX11 syndrome, separating SOX11 syndrome from other BAFopathies."

Direct molecular evidence that the SOX11 entity is separable from the BAFopathies, supporting a split rather than a lump against classical Coffin-Siris syndrome.

Disrupted Ocular Morphogenesis

SOX11 is required for normal eye development. Reduced SOX11 activity can produce structural eye malformations (microphthalmia, iris coloboma) in a minority of affected individuals, which is why the OMIM/MONDO disease name carries the "with or without ocular malformations" qualifier.

eye development GO:0001654 ↓ DECREASED

eye UBERON:0000970

Show evidence (2 references)

PMID:26543203 SUPPORT Model Organism

"There is also evidence that SOX11 plays a role in ocular development. Sox11 knockdown in zebrafish induces microphthalmia with or without iris coloboma."

Model-organism basis for the ocular arm of the SOX11 phenotype.

PMID:26543203 SUPPORT Human Clinical

"Ocular abnormalities were present in both deletion and mutation cases; case 1 had right microphthalmia"

Human observation of structural microphthalmia in a SOX11-only deletion carrier, matching the animal-model prediction.

Impaired Hypothalamic-Pituitary Gonadotropic Axis Development

A subset of affected individuals have idiopathic hypogonadotropic hypogonadism, with anosmic (Kallmann-like) and normosmic forms, plus additional anterior pituitary hormone deficiencies and structural hypothalamic/pituitary and olfactory-bulb defects. This indicates that SOX11 is required for development of the GnRH neuroendocrine axis at both hypothalamic and pituitary levels.

hypothalamic gonadotropin-releasing hormone neuron CL:0011111

hypothalamus development GO:0021854 ↓ DECREASED

hypothalamus UBERON:0001898

Show evidence (2 references)

PMID:35341651 SUPPORT Human Clinical

"Idiopathic hypogonadotropic hypogonadism was confirmed as a feature of SOX11 syndrome."

Establishes hypogonadotropic hypogonadism as a bona fide feature of the SOX11 entity in a 38-patient cohort.

PMID:39290158 SUPPORT Human Clinical

"Deleterious SOX11 variants cause IHH and other pituitary hormone deficiencies, suggesting that the human SOX11-associated disorder may stem from both hypothalamic and pituitary level defects."

Localises the endocrine lesion to both hypothalamic and pituitary levels based on a 1810-proband IHH cohort.

Impaired Cochlear Nerve Development

SOX11 is highly expressed in the developing inner ear and is required for sensory neuron survival and axonal outgrowth. Reduced dosage can produce cochlear nerve hypoplasia or aplasia with sensorineural hearing loss despite grossly normal inner ear structures.

cochlear nerve UBERON:0004727

Show evidence (2 references)

PMID:35642566 SUPPORT Model Organism

"Homozygous ablation of SOX11 in a mouse model resulted in a reduction in sensory neuron survival and decreased axonal growth. A heterozygous knockout mice model had hearing impairment with grossly normal inner ear structures like the two probands reported."

Mouse data connect SOX11 dosage to sensory neuron survival and hearing impairment with structurally normal inner ears.

PMID:35642566 SUPPORT Human Clinical

"They have unilateral sensorineural hearing loss due to cochlear nerve deficiency confirmed on MRI."

Human imaging confirmation of cochlear nerve deficiency in two unrelated SOX11 probands.

Elevated Hedgehog Signalling in the Developing Eye

A mechanistically counter-intuitive arm: loss of SOX11 raises rather than lowers signalling output downstream, because SOX11 normally acts as a negative regulator of shha transcription during ocular morphogenesis. The resulting excess Hedgehog signalling causes failure of choroid fissure closure. In zebrafish the ocular phenotype is rescued by the Hedgehog inhibitor cyclopamine, so the lesion is pathway hyperactivity, not loss.

smoothened signaling pathway GO:0007224 ↑ INCREASED

eye UBERON:0000970

Downstream

Disrupted Ocular Morphogenesis Excess Hedgehog signalling disrupts choroid fissure closure and lens development, producing coloboma and microphthalmia.

Show evidence (1 reference)

PMID:25010521 SUPPORT Model Organism

"Sox11 Negatively Regulates Hedgehog Signaling"

Establishes the direction of the effect: SOX11 restrains Hedgehog signalling, so SOX11 loss produces pathway hyperactivity in the eye.

Reduced FGF9-Driven Mandibular Mesenchyme Proliferation

SOX11 directly regulates Fgf9 expression, and Fgf9 in turn drives Cyclin D1-dependent proliferation of the developing mandibular mesenchyme. Loss of SOX11 reduces this proliferation.

cell population proliferation GO:0008283 ↓ DECREASED

Downstream

Mandibular Hypoplasia with Secondary Palatal Shelf Obstruction Reduced mandibular mesenchyme proliferation produces mandibular hypoplasia.

Show evidence (2 references)

PMID:26826126 SUPPORT Model Organism

"We found that loss of Sox11led to reduced cell proliferation in the developing mandibular mesenchyme via Cyclin D1, leading to mandibular hypoplasia, which blocks tongue descent."

Identifies the proliferative defect and its immediate anatomical consequence in the Sox11 mouse mutant.

PMID:26826126 SUPPORT Model Organism

"we show, using in vitro assays, that Sox11 directly regulates the expression of Fgf9 and that application of FGF9 protein to Sox11-deficient palatal shelves restores the rate of BrdU incorporation."

Establishes FGF9 as the direct SOX11 target mediating the proliferative arm, with rescue on FGF9 replacement.

Mandibular Hypoplasia with Secondary Palatal Shelf Obstruction

The cleft palate seen in SOX11 deficiency is mechanistically secondary, not a primary palatal-shelf defect. The shelves themselves retain fusion and elevation competence; mandibular hypoplasia mispositions the tongue, which physically obstructs palatal shelf elevation. The resulting picture resembles the Pierre Robin sequence.

roof of mouth development GO:0060021 ↕ DYSREGULATED

Show evidence (1 reference)

PMID:26826126 SUPPORT Model Organism

"As in the wild type, the palatal shelves in the Sox11 mutant undergo outgrowth in a downward direction and exhibit potential for fusion and elevation. However, mutant palatal shelves encounter clefting, which is associated with a malpositioned tongue that results in physical obstruction of..."

Directly demonstrates that the clefting is obstructive and secondary rather than a primary defect of the palatal shelves.

Disrupted Nephrogenic Gdnf Domain Restriction

SOX11 is expressed in both mesenchymal and epithelial components of the early kidney anlagen and restricts the rostral extent of the Gdnf expression domain in the nephrogenic cord. Loss of Sox11 extends that domain and produces duplex kidney; later, SOX11 is required in the intermediate nephron segment for elongation of Henle's loop.

kidney development GO:0001822 ↕ DYSREGULATED

kidney UBERON:0002113

Show evidence (2 references)

PMID:29459093 SUPPORT Model Organism

"Deletion of Sox11 in mice causes an extension of the domain expressing Gdnf within rostral regions of the nephrogenic cord and results in duplex kidney formation."

Defines the developmental mechanism linking Sox11 loss to a structural kidney malformation.

PMID:29459093 PARTIAL Human Clinical

"mutation analysis in a cohort of patients suffering from CAKUT identified a series of rare SOX11 variants, one of which interferes with the transactivation capacity of the SOX11 protein"

Human variant evidence linking SOX11 to CAKUT. Marked PARTIAL because these were rare variants in a CAKUT cohort rather than individuals with the full SOX11 neurodevelopmental syndrome.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

Cardiovascular 1

Coarctation of Aorta Coarctation of aorta HP:0001680

Show evidence (1 reference)

PMID:28787104 SUPPORT Human Clinical

"He showed the CSS phenotype and coarctation of the aorta. Sox11 is known to be associated with cardiac outflow development in mouse studies."

Single-case report; no frequency band is assigned. The mouse outflow-tract role provides mechanistic plausibility.

Digestive 1

Feeding Difficulties Feeding difficulties HP:0011968

Show evidence (1 reference)

PMID:26543203 SUPPORT Human Clinical

"Microcephaly, low birth weight and neonatal feeding difficulties associated with hypotonia were frequent findings."

Describes neonatal feeding difficulty as a frequent finding among individuals with de novo SOX11 variants.

Ear 1

Sensorineural Hearing Impairment Sensorineural hearing impairment HP:0000407

Show evidence (2 references)

PMID:36369738 SUPPORT Human Clinical

"Deleterious SOX11 variants can result in sensorineural hearing loss with inner ear malformation, potentially extending the array of phenotypes associated with these pathogenic variants."

Two Chinese probands with de novo SOX11 variants and syndromic sensorineural hearing loss.

PMID:35642566 SUPPORT Human Clinical

"They have unilateral sensorineural hearing loss due to cochlear nerve deficiency confirmed on MRI."

Independent report of sensorineural hearing loss with a defined cochlear-nerve mechanism.

Endocrine 3

Delayed Puberty Delayed puberty HP:0000823

Show evidence (1 reference)

PMID:42168980 SUPPORT Human Clinical

"We report a 13-year-old Chinese girl who presented with delayed puberty (Tanner B1, PH1), infantile uterus and low basal gonadotropins."

Delayed puberty as the presenting feature of SOX11-related hypogonadotropic hypogonadism.

Hypogonadotropic Hypogonadism Hypogonadotropic hypogonadism HP:0000044

Show evidence (2 references)

PMID:35341651 SUPPORT Human Clinical

"Idiopathic hypogonadotropic hypogonadism was confirmed as a feature of SOX11 syndrome."

Confirms hypogonadotropic hypogonadism as an established feature in the largest deep-phenotyped SOX11 cohort. No frequency band is assigned because the abstract does not report a denominator.

PMID:39333428 SUPPORT Human Clinical

"HH was confirmed in two female patients with primary amenorrhea, nonvisualized/prepubertal size of the uterus, and nonvisualized ovaries."

Independent confirmation with explicit endocrine and imaging criteria.

Hypothyroidism Hypothyroidism HP:0000821

Show evidence (1 reference)

PMID:39290158 SUPPORT Human Clinical

"additional endocrine defects including anosmic and normosmic forms of IHH, GH deficiency, pituitary and hypothalamic structural defects, and hypothyroidism"

Hypothyroidism listed among the endocrine defects in SOX11 variant carriers.

Eye 3

Oculomotor Apraxia Oculomotor apraxia HP:0000657

Show evidence (2 references)

PMID:26543203 SUPPORT Human Clinical

"cases 7 and 9 had oculomotor apraxia"

Direct observation of oculomotor apraxia in two individuals in the 2p25 deletion and de novo variant cohort.

PMID:40933692 PARTIAL Human Clinical

"the most prevalent phenotype was ocular motor disorder (15/58, 29.31%)"

Systematic pooled review of 58 published SOX11 cases finds ocular motor disorder to be the most prevalent ophthalmological phenotype. Marked PARTIAL and no band assigned to this node: "ocular motor disorder" is a broader category than Cogan-type oculomotor apraxia specifically, so 15/58 (29.31%) is an upper bound on the apraxia frequency rather than a denominator for it. The pooled ophthalmological figure is banded on the Ophthalmological Malformation entry instead.

Coloboma Coloboma HP:0000589

Show evidence (2 references)

PMID:26543203 SUPPORT Model Organism

"Sox11 knockdown in zebrafish induces microphthalmia with or without iris coloboma."

Model-organism evidence for the coloboma arm. Human coloboma in SOX11 carriers is documented in the larger cohort but not in a quotable abstract, so no frequency band is assigned.

PMID:25010521 SUPPORT Model Organism

"Sox11 Negatively Regulates Hedgehog Signaling"

Provides the mechanism (Hedgehog de-repression) by which SOX11 loss produces failure of choroid fissure closure.

Microphthalmia Microphthalmia HP:0000568

Show evidence (1 reference)

PMID:26543203 SUPPORT Human Clinical

"Ocular abnormalities were present in both deletion and mutation cases; case 1 had right microphthalmia"

Unilateral microphthalmia in a carrier of a deletion containing SOX11 only, so the finding is attributable to SOX11 loss.

Genitourinary 4

Renal and Urinary Tract Anomalies Abnormality of the kidney HP:0000077

Show evidence (2 references)

PMID:24886874 SUPPORT Human Clinical

"Abdominal echography showed her left kidney was slightly small in size."

Renal anomaly in the first index SOX11 proband.

PMID:29459093 SUPPORT Model Organism

"Here we show that the transcription factor SOX11 is a crucial regulator of kidney development."

Mechanistic support for a genuine SOX11-dependent renal developmental role underlying the human anomalies.

Primary Amenorrhea Primary amenorrhea HP:0000786

Show evidence (1 reference)

PMID:39333428 SUPPORT Human Clinical

"HH was confirmed in two female patients with primary amenorrhea, nonvisualized/prepubertal size of the uterus, and nonvisualized ovaries."

Direct report of primary amenorrhoea in two affected females.

Micropenis Micropenis HP:0000054

Show evidence (1 reference)

PMID:39333428 SUPPORT Human Clinical

"Two of the male patients presented with micropenis, two had cryptorchidism, and one had decreased testicular size, which are suggestive findings of HH."

Direct report of micropenis in two affected males.

Cryptorchidism Cryptorchidism HP:0000028

Show evidence (2 references)

PMID:39333428 SUPPORT Human Clinical

"Two of the male patients presented with micropenis, two had cryptorchidism, and one had decreased testicular size, which are suggestive findings of HH."

Direct report of cryptorchidism in two affected males.

PMID:35938035 SUPPORT Human Clinical

"Cryptorchidism + N/A + 5/6"

Table 1 pools the published SOX11 literature and gives cryptorchidism in 5/6. No frequency band is assigned: the denominator of 6 is the subset of the 28 reported males in whom genital examination was documented, so 5/6 is a reporting-conditional figure rather than a cohort frequency, and converting it to a band would overstate what the table supports.

Head and Neck 3

Microcephaly FREQUENT Microcephaly HP:0000252

Show evidence (3 references)

PMID:39333428 SUPPORT Human Clinical

"microcephaly (4/7), short stature (4/7), hypotonia (4/7), and clinodactyly of the 5th fingers (5/7)"

Microcephaly in 4/7 (57%) maps to the FREQUENT (30-79%) band.

PMID:26543203 SUPPORT Human Clinical

"Microcephaly was reported in all but two."

In the seven 2p25 deletion carriers, microcephaly was present in five of seven, consistent with the FREQUENT band.

PMID:35938035 SUPPORT Human Clinical

"Microcephaly −− + 11/28"

Table 1 pools the published SOX11 literature (n = 58 reported patients) and gives microcephaly in 11/28 individuals with a reported head circumference. 11/28 = 39%, which confirms the FREQUENT (30-79%) band on a four-fold larger denominator than the n=7 series above.

Anosmia Anosmia HP:0000458

Show evidence (1 reference)

PMID:39290158 SUPPORT Human Clinical

"The phenotypic spectrum of SOX11 variant carriers revealed additional endocrine defects including anosmic and normosmic forms of IHH, GH deficiency, pituitary and hypothalamic structural defects, and hypothyroidism."

Establishes that both anosmic and normosmic IHH occur in SOX11 variant carriers.

Cleft Palate Cleft palate HP:0000175

Show evidence (1 reference)

PMID:29437512 SUPPORT Human Clinical

"This boy had a cleft palate, a feature not previously seen in other patients with SOX11 mutations."

Single-case report; no frequency band is assigned because this is an isolated observation.

Integument 2

Hypoplastic Fifth Fingernail OCCASIONAL Hypoplastic fifth fingernail HP:0008398

Show evidence (2 references)

PMID:35938035 SUPPORT Human Clinical

"Hypoplastic nails −− − 6/55"

Table 1 pools the published SOX11 literature (n = 58 reported patients) and gives hypoplastic nails in 6/55. 6/55 = 11%, which falls in the OCCASIONAL (5-29%) band. The pooled row is for hypoplastic nails generally; in this disorder the reported nail hypoplasia is overwhelmingly fifth-digit, which is how it is curated here.

PMID:26543203 SUPPORT Human Clinical

"Hypoplasia of the distal phalanx of the fifth finger, broad halluces,"

Documents fifth-digit distal phalanx and nail hypoplasia among individuals with de novo SOX11 variants.

Hypertrichosis Hypertrichosis HP:0000998

Show evidence (1 reference)

PMID:24886874 SUPPORT Human Clinical

"they do share features in common, namely, hypertrichosis, arched eyebrows, low-set ears, auricular back-rotationand full cheeks"

Hypertrichosis listed among the features shared by the two index SOX11 probands.

Musculoskeletal 1

Hypotonia FREQUENT Hypotonia HP:0001252

Show evidence (1 reference)

PMID:39333428 SUPPORT Human Clinical

"microcephaly (4/7), short stature (4/7), hypotonia (4/7), and clinodactyly of the 5th fingers (5/7)"

Hypotonia in 4/7 (57%) maps to the FREQUENT (30-79%) band.

Nervous System 5

Global Developmental Delay VERY_FREQUENT Global developmental delay HP:0001263

Show evidence (2 references)

PMID:39333428 SUPPORT Human Clinical

"The main clinical features included neurodevelopmental delay (7/7) and intellectual disability (5/7), autism/attention deficit hyperactivity disorder (5/7), microcephaly (4/7), short stature (4/7), hypotonia (4/7), and clinodactyly of the 5th fingers (5/7)."

Neurodevelopmental delay in 7/7 (100%) of this consecutive case series supports the VERY_FREQUENT band; the cohort is small (n=7), so the band is corroborated by the qualitative statements in PMID:26543203 that all deletion and point-variant carriers had developmental delay.

PMID:35938035 SUPPORT Human Clinical

"DD − + + 36/37"

Table 1 pools the published SOX11 literature (n = 58 reported patients) and gives developmental delay in 36/37 individuals for whom it was reported. 36/37 = 97%, confirming the VERY_FREQUENT (80-99%) band on a denominator five times larger than the n=7 series above.

Intellectual Disability VERY_FREQUENT Intellectual disability HP:0001249

Show evidence (3 references)

PMID:35938035 SUPPORT Human Clinical

"ID N/R + + 38/40"

Table 1 of this report pools the published SOX11 literature (n = 58 reported patients) and gives intellectual disability in 38/40 individuals for whom cognition was reported. 38/40 = 95%, which falls in the VERY_FREQUENT (80-99%) band. This pooled denominator supersedes the n=7 series below for band assignment.

PMID:39333428 SUPPORT Human Clinical

"The main clinical features included neurodevelopmental delay (7/7) and intellectual disability (5/7)"

Intellectual disability in 5/7 (71%) of this small consecutive series. Retained as corroborating evidence only; the band is set from the pooled 38/40 denominator above rather than from this n=7 figure.

PMID:37558216 SUPPORT Human Clinical

"SOX11 abnormalities feature a distinctive disorder characterised by severe ID, high incidence of microcephaly and low frequency of congenital malformations"

Review of 32 detailed published cases characterising the severity of the cognitive phenotype.

Cerebellar Vermis Hypoplasia Cerebellar vermis hypoplasia HP:0001320

Show evidence (1 reference)

PMID:26543203 SUPPORT Human Clinical

"A brain MRI detected hypoplasia of the inferior aspect of the cerebellar vermis. Array CGH (180k, Agilent) was normal. Exome sequencing identified a de novo, nonsense variant in SOX11"

Case 10 of this series: cerebellar vermis hypoplasia in an individual with a normal array CGH and an isolated de novo SOX11 nonsense variant. No frequency band is assigned - this is a single reported individual and no denominator for imaged SOX11 patients is available in a quotable source.

Autistic Behavior VERY_FREQUENT Autistic behavior HP:0000729

Show evidence (1 reference)

PMID:37924570 SUPPORT Human Clinical

"Most (90 %) were found to exhibit clinically relevant levels of autistic traits, with 62 % scoring in the "severe" range, though social motivation was observed to be a relative strength in the cohort overall."

Standardised SRS-2 assessment of 21 individuals gives a direct quantitative frequency of 90%, in the VERY_FREQUENT (80-99%) band.

Attention Deficit Hyperactivity Disorder Attention deficit hyperactivity disorder HP:0007018

Show evidence (1 reference)

PMID:39333428 PARTIAL Human Clinical

"autism/attention deficit hyperactivity disorder (5/7)"

Supports the association, but the source counts autism and ADHD together, so no separate ADHD frequency band can be assigned.

Growth 2

Short Stature FREQUENT Short stature HP:0004322

Show evidence (2 references)

PMID:39333428 SUPPORT Human Clinical

"microcephaly (4/7), short stature (4/7), hypotonia (4/7)"

Short stature in 4/7 (57%) maps to the FREQUENT (30-79%) band.

PMID:35938035 SUPPORT Human Clinical

"Short stature + − + 10/30"

Table 1 pools the published SOX11 literature (n = 58 reported patients) and gives short stature in 10/30 individuals with a reported height. 10/30 = 33%, confirming the FREQUENT (30-79%) band on a four-fold larger denominator than the n=7 series above.

Growth Delay Growth delay HP:0001510

Show evidence (1 reference)

PMID:35642566 SUPPORT Human Clinical

"phenotypic manifestations of CSS including global developmental delay, growth deficiency, and hypoplastic nails"

Growth deficiency reported as a manifestation in two SOX11 probands.

Other 7

Ophthalmological Malformation FREQUENT Abnormality of the eye HP:0000478

Show evidence (1 reference)

PMID:40933692 SUPPORT Human Clinical

"Quantitative analysis of the ophthalmological phenotypic spectrum of the 58 cases (including our proband) revealed that almost half (26/58, 44.83%) presented ophthalmological malformations"

Systematic PRISMA-based review pooling 57 published SOX11 cases plus the authors' proband, restricted to single-nucleotide variants after excluding contiguous-gene CNV cases. 26/58 = 44.83%, which falls in the FREQUENT (30-79%) band. This is the first denominator-based ocular frequency for the disorder and is what the OMIM/MONDO "with or without ocular malformation" qualifier had previously left unquantified.

Impaired Adaptive Behaviour

Show evidence (1 reference)

PMID:37924570 PARTIAL Human Clinical

"Most were found to have borderline (33 %) or mild (39 %) impairment in adaptive behaviour, with more difficulties in communication and daily living than socialisation in the cohort overall."

Supports the adaptive-behaviour profile. Marked PARTIAL because the HPO term for borderline intellectual functioning is an imperfect proxy for the Vineland adaptive-behaviour construct actually measured.

Expressive Language Delay Expressive language delay HP:0002474

Show evidence (1 reference)

PMID:26543203 SUPPORT Human Clinical

"All had developmental delay, with particularly marked speech delay."

Identifies speech delay as a disproportionately affected domain in the 2p25 deletion cohort.

Clinodactyly of the 5th Finger OCCASIONAL Clinodactyly of the 5th finger HP:0004209

Show evidence (2 references)

PMID:35938035 SUPPORT Human Clinical

"Clinodactyly 5th ﬁnger −− 10/55"

Table 1 pools the published SOX11 literature (n = 58 reported patients) and gives fifth-finger clinodactyly in 10/55. 10/55 = 18%, which falls in the OCCASIONAL (5-29%) band. This pooled denominator, not the n=7 series below, governs the band: the 5/7 (71%) figure is an outlier from a small consecutive series.

PMID:39333428 SUPPORT Human Clinical

"and clinodactyly of the 5th fingers (5/7)"

Fifth-finger clinodactyly in 5/7 of this seven-patient series. Retained as a direct observation; it is not used for the band because the pooled 55-patient denominator above is eight times larger.

Hypoplasia of the Olfactory Bulb Hypoplasia of the olfactory bulb HP:0040326

Show evidence (1 reference)

PMID:42168980 SUPPORT Human Clinical

"Olfactory and pituitary MRI revealed bilateral olfactory-bulb/nerve hypoplasia and a pituitary height of 3.4 mm, fulfilling Kallmann-syndrome criteria."

Imaging documentation of olfactory bulb hypoplasia in a SOX11 variant carrier.

Iris Coloboma Iris coloboma HP:0000612

Show evidence (1 reference)

PMID:26543203 PARTIAL Human Clinical

"variants in SOX11 have also been identified in two individuals with iris coloboma and no neurodevelopmental phenotype"

Marked PARTIAL: the two individuals with iris coloboma had no neurodevelopmental phenotype and carried variants outside the HMG domain, so this may represent a distinct, milder allelic presentation rather than a feature of the full syndrome.

Cochlear Nerve Hypoplasia Cochlear nerve hypoplasia HP:0034585

Show evidence (1 reference)

PMID:35642566 SUPPORT Human Clinical

"We propose cochlear nerve deficiency as a new phenotypic feature of SOX11-related CSS."

Explicit proposal of cochlear nerve deficiency as a SOX11-associated feature, based on two MRI-confirmed probands.

🧬

Genetic Associations

SOX11 (Heterozygous pathogenic variants in SOX11 are the sole established cause of this disorder. The MONDO anchor MONDO:0014376 carries a single RO:0004003 (has material basis in germline mutation in) relation to HGNC:11191 (SOX11).)

Gene: SOX11 hgnc:11191 relationship_type: CAUSATIVE variant_origin: DE_NOVO

Show evidence (3 references)

PMID:24886874 SUPPORT Human Clinical

"we apply whole-exome sequencing (WES) to 92 CSS patients, and identify two de novo SOX11 mutations in two unrelated patients."

Original gene-disease assertion for SOX11 based on trio whole-exome sequencing.

PMID:42168980 SUPPORT Human Clinical

"Thirty unique variants were identified, 17/30 clustering within the HMG domain and 15/18 proven de-novo."

Summarises the variant spectrum across the published SOX11 literature.

PMID:26543203 SUPPORT Human Clinical

"SOX11 is a single exon gene. Nonsense-mediated decay (NMD) may not occur with mutations in the final exon of a gene"

Explains the single-exon architecture and its implication for the fate of truncating transcripts.

💊

Medical Actions

Multidisciplinary Developmental and Behavioural Support

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Standard management for developmental delay and intellectual disability: early intervention, special education, speech and language therapy, physiotherapy, occupational therapy, and behavioural assessment and support for ADHD, anxiety, aggression, and autistic features. No disease-modifying therapy exists.

Show evidence (1 reference)

PMID:23556151 SUPPORT Other

"Standard treatment for developmental delay / intellectual disability, epilepsy, tics, sleep disturbance, scoliosis, joint laxity, knee subluxations, obesity, refractive error, strabismus, ptosis, hearing loss, congenital heart defects, undervirilization, inguinal hernia, frequent infections, and..."

GeneReviews management recommendation for the Coffin-Siris syndrome spectrum, of which SOX11 is one of the 14 listed genes. Expert-consensus guidance rather than trial data, hence evidence_source OTHER.

Feeding Therapy and Nutritional Support

Action: nutritional support Ontology label: Nutritional Support NCIT:C15433

Feeding therapy for infantile feeding difficulty, with consideration of gastrostomy tube placement when feeding problems persist.

Show evidence (1 reference)

PMID:23556151 SUPPORT Other

"Feeding therapy with consideration of placement of gastrostomy tube in those with persistent feeding issues."

GeneReviews management recommendation matching the feeding difficulty documented in SOX11 cohorts.

Pulsatile GnRH Therapy for Hypogonadotropic Hypogonadism

Action: Pharmacotherapy NCIT:C15986

Agent: gonadorelin CHEBI:5520

Pulsatile gonadotropin-releasing hormone (GnRH pump) therapy to induce puberty and restore gonadotropin secretion in SOX11-related hypogonadotropic hypogonadism. Reported to restore gonadotropin output within 72 hours in a single treated proband; this is single-case evidence, not trial evidence.

Mechanism Target:

BYPASSES Impaired Hypothalamic-Pituitary Gonadotropic Axis Development — Exogenous pulsatile GnRH bypasses the deficient hypothalamic GnRH pulse generator and drives pituitary gonadotropin release.

Show evidence (1 reference)

PMID:42168980 SUPPORT Human Clinical

"GnRH-pump therapy restored gonadotropin output within 72 h."

Single-patient report of biochemical response to pulsatile GnRH in a SOX11 variant carrier with Kallmann-criteria hypogonadotropic hypogonadism.

Endocrine, Ophthalmological and Audiological Surveillance

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Baseline and periodic endocrine assessment (including pubertal staging and anterior pituitary hormone screening), MRI of the olfactory tracts and pituitary, annual ophthalmology and audiology evaluation. MRI is specifically useful for delineating cochlear nerve deficiency.

Show evidence (3 references)

PMID:42168980 SUPPORT Human Clinical

"mandating comprehensive baseline evaluation-including endocrine assessment, neurodevelopmental screening, and MRI of olfactory tracts and pituitary-regardless of initial presentation"

Explicit surveillance recommendation from the SOX11-related-disorder literature review.

PMID:35642566 SUPPORT Human Clinical

"Magnetic resonance imaging is useful in delineating the cochlear nerve deficiency and other CSS-related brain malformations."

Supports MRI as the modality for detecting the cochlear nerve deficiency arm of the phenotype.

PMID:23556151 SUPPORT Other

"Annually or as clinically indicated, ophthalmology evaluation and vision assessment; audiology evaluation."

GeneReviews surveillance schedule for the Coffin-Siris spectrum, directly relevant to the ocular and auditory features of the SOX11 entity.

Genetic Counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Autosomal dominant counselling. Most cases are de novo, giving a low but non-zero recurrence risk from germline mosaicism; parental testing is required because transmission from a mildly affected parent has been reported. Prenatal and preimplantation genetic testing are possible once the familial variant is known.

Show evidence (2 references)

PMID:23556151 SUPPORT Other

"If the CSS-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible."

GeneReviews genetic counselling guidance for the Coffin-Siris spectrum including SOX11.

PMID:33785884 SUPPORT Human Clinical

"Maternal transmission of a mild Coffin-Siris syndrome phenotype caused by a SOX11 missense variant."

Justifies parental testing rather than assuming de novo occurrence.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from SOX11-Related Neurodevelopmental Disorder:

Coffin-Siris syndrome due to BAF (SWI/SNF) core-subunit variants

Overlapping Features Classical Coffin-Siris syndrome is caused by heterozygous variants in genes encoding subunits of the BAF/SWI-SNF chromatin remodelling complex (ARID1A, ARID1B, ARID2, DPF2, SMARCA4, SMARCB1, SMARCC2, SMARCD1, SMARCE1, BICRA) plus PHF6. SOX11 shares the clinical label "Coffin-Siris syndrome 9" but is a transcription factor acting DOWNSTREAM of the PAX6-BAF complex, not a component of it. This is the single most important named-entity distinction for this entry: BAF core-subunit cohort phenotype data must NOT be attributed to SOX11.

Distinguishing Features

Molecular criterion - the causal variant is in SOX11 (2p25.2), not in a BAF subunit gene; SOX11 and BAF-subunit variants are mutually exclusive in Coffin-Siris cohorts.
Episignature - blood DNA methylation profiling separates SOX11 syndrome from the BAFopathies.
Mechanism - SOX11 is transcriptionally downstream of the PAX6-BAF complex (BRG1/SMARCA4 binds the SOX11 promoter), so SOX11 loss is a narrower lesion than loss of the remodeller itself.
Severity - BAF core-subunit disease tends to be more severe; SOX11 accounts for only about 2% of Coffin-Siris cohorts and clusters at the milder dysmorphic end while carrying a heavier microcephaly burden.
Epilepsy burden - GeneReviews reports epilepsy in about half of Coffin-Siris syndrome overall, whereas epilepsy is distinctly uncommon in reported SOX11 cohorts. Importing the Coffin-Siris epilepsy frequency into a SOX11 entry would materially misstate the phenotype, so no epilepsy frequency is curated here.
Coarse facies - coarse facial features are a hallmark of ARID1B Coffin-Siris syndrome and are characteristically absent in SOX11 disease, making facial gestalt a discriminator in the opposite direction to the historical CSS9 label.
Cancer surveillance - the ARID1A-specific AFP/hepatoblastoma surveillance recommendation in the Coffin-Siris GeneReviews chapter is gene-specific and is deliberately NOT applied to SOX11; no cancer predisposition has been reported with germline SOX11 variants.
Direction of the SOX11-BAF relationship is not fixed - in germline neurodevelopmental disease SOX11 sits downstream of PAX6-BAF, whereas in adrenergic neuroblastoma SOX11 acts upstream of and regulates SWI/SNF core components including SMARCA4 and ARID1A. The somatic over-expression biology is separate and must not be imported into this germline entry.

Show evidence (6 references)

PMID:35341651 SUPPORT Human Clinical

"SOX11 syndrome is a distinct clinical entity with characteristic clinical features and episignature differentiating it from BAFopathies."

Primary evidence for keeping SOX11 split from the BAFopathies rather than lumping it into classical Coffin-Siris syndrome.

PMID:24886874 SUPPORT Human Clinical

"SOX11 is the downstream transcriptional factor of the PAX6-BAF complex, highlighting the importance of the BAF complex and SOX11 transcriptional network in brain development."

Establishes the downstream (non-core-subunit) position of SOX11 relative to the BAF complex.

PMID:24886874 SUPPORT Human Clinical

"mutations of SOX11 and other BAF subunit genes are mutually exclusive in CSS."

Mutual exclusivity confirms these are separate molecular causes rather than co-occurring lesions.

+ 3 more references

SOX4-related neurodevelopmental disorder (Coffin-Siris syndrome 10) Not Yet Curated MONDO:0032791

Overlapping Features SOX4 is the closest SoxC paralogue of SOX11 and is also listed as a Coffin-Siris syndrome gene in GeneReviews. The phenotypes overlap substantially, so gene identity - not clinical gestalt - is the discriminator.

Distinguishing Features

The causal variant is in SOX4, not SOX11; the two are separate MONDO/OMIM entities despite overlapping presentations.
SOX11-specific findings such as the SOX11 blood methylation episignature and the documented hypogonadotropic hypogonadism association are not established for SOX4.

Show evidence (1 reference)

PMID:23556151 SUPPORT Other

"ARID1B, ARID2, BICRA, DPF2, PHF6, SMARCA2, SMARCA4, SMARCB1, SMARCC2, SMARCD1, SMARCE1, SOX4, or SOX11."

GeneReviews lists SOX4 and SOX11 as separate Coffin-Siris-spectrum genes, confirming they are distinct entities that share a clinical label.

SOX2-related anophthalmia syndrome

Overlapping Features SOX2 haploinsufficiency causes anophthalmia/microphthalmia with developmental delay. Because SOX11 loss can also produce microphthalmia and developmental delay, SOX2 is a realistic clinical and named-entity confusion, but SOX2 belongs to the SoxB1 group and is a different gene at a different locus.

Distinguishing Features

Severe bilateral anophthalmia is characteristic of SOX2 and is not a feature of SOX11-related disorder, in which ocular malformation is infrequent and usually milder.
Fifth-digit nail/phalanx hypoplasia, hypogonadotropic hypogonadism with olfactory bulb hypoplasia, and the SOX11 episignature point to SOX11.

Show evidence (1 reference)

PMID:24886874 SUPPORT Human Clinical

"of other SOX genes ( SOX2, SOX9 and SOX10) is known to cause human diseases"

Confirms SOX2 as a separate SOX-family disease gene, distinguishing it from SOX11.

Pitt-Hopkins syndrome (TCF4) MONDO:0012589

Overlapping Features A subset of individuals with SOX11 variants present with a clinical gestalt indistinguishable from Pitt-Hopkins syndrome, so a negative TCF4 result in a clinically diagnosed Pitt-Hopkins patient should prompt SOX11 testing.

Distinguishing Features

Pitt-Hopkins syndrome is caused by TCF4 haploinsufficiency; a normal TCF4 result with a clinical Pitt-Hopkins gestalt should trigger broader sequencing.
Approximately 22% of well-characterised published SOX11 cases have a Pitt-Hopkins-overlapping presentation.

Show evidence (1 reference)

PMID:37558216 SUPPORT Human Clinical

"By reviewing both clinically and genetically 32 out of 82 subjects reported in the literature with SOX11 variants, for whom detailed information are provided, we found that 7/32 (22%) had a clinical presentation overlapping PTHS."

Quantifies the Pitt-Hopkins overlap and establishes SOX11 as a differential for TCF4-negative Pitt-Hopkins.

Contiguous-gene 2p25 deletion phenotypes (MYCN, MYT1L)

Overlapping Features Larger 2p25 deletions that remove SOX11 can also remove MYCN (Feingold syndrome) or MYT1L, so the phenotype of a deletion carrier may not be attributable to SOX11 alone.

Distinguishing Features

Deletion breakpoint mapping determines which additional genes are lost; deletions containing SOX11 alone isolate the SOX11 contribution.
MYT1L-only deletions tend to cause macrocephaly, whereas SOX11-containing deletions cause microcephaly.

Show evidence (2 references)

PMID:26543203 SUPPORT Human Clinical

"Several other genes within the deleted 2p25 regions could contribute to the observed phenotypes."

Explicit caution against attributing all deletion-carrier features to SOX11 haploinsufficiency.

PMID:26543203 SUPPORT Human Clinical

"This suggests that SOX11 haploinsufficiency may exert a powerful, negative influence on brain growth."

The opposite head-size direction of MYT1L-only versus SOX11-containing deletions is what isolates the SOX11 contribution to microcephaly.

{ }

Source YAML

click to show

name: SOX11-Related Neurodevelopmental Disorder
creation_date: "2026-07-31T00:00:00Z"
category: Mendelian
synonyms:
- Coffin-Siris syndrome 9
- CSS9
- SOX11 syndrome
- IDDMOH
- intellectual developmental disorder, autosomal dominant 27
- MRD27
description: >
  SOX11-related neurodevelopmental disorder is a rare autosomal dominant
  condition caused by heterozygous de novo loss-of-function or missense
  variants in SOX11 (2p25.2), or by microdeletions encompassing the gene.
  SOX11 encodes a single-exon SoxC-group high-mobility-group (HMG) box
  transcription factor that drives neural progenitor proliferation, neuronal
  differentiation, and neuronal survival during fetal brain development.
  Core clinical features are neurodevelopmental delay and intellectual
  disability, microcephaly, hypotonia, short stature, autistic traits, and
  mild distal-limb findings (fifth-finger clinodactyly, hypoplastic fifth
  nails). A subset of individuals have ocular malformations (microphthalmia,
  iris coloboma) or hypogonadotropic hypogonadism, which is why OMIM/MONDO
  name the entity "intellectual developmental disorder with microcephaly and
  with or without ocular malformations or hypogonadotropic hypogonadism".
  The disorder is repeatedly labelled "Coffin-Siris syndrome 9" in the
  literature because the first two probands had a mild Coffin-Siris-like
  presentation, but SOX11 is a transcriptional effector acting DOWNSTREAM of
  the PAX6-BAF (SWI/SNF) complex rather than a BAF core subunit, and SOX11
  cases carry a blood DNA methylation episignature that separates them from
  the BAFopathies.
disease_term:
  preferred_term: intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism
  term:
    id: MONDO:0014376
    label: intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism
parents:
- Neurodevelopmental disorder
- Autosomal dominant disease
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0100626
      label: SOX11-related complex neurodevelopmental disorder with or without congenital anomalies
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >
      MONDO:0100626 is the newer, ClinGen-grounded term for the same SOX11
      entity and carries the same RO:0004003 relation to HGNC:11191 (SOX11).
      MONDO lists this entry's anchor label ("intellectual developmental
      disorder with microcephaly and with or without ocular malformations or
      hypogonadotropic hypogonadism") as a NARROW synonym of MONDO:0100626,
      hence skos:broadMatch. This entry is deliberately anchored on
      MONDO:0014376 (the OMIM:615866-xrefed term named in the curation
      request); MONDO:0100626 is the term a future re-anchoring should use.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No formal population prevalence or incidence estimate has been published for
    this disorder, and none is asserted here. Roughly 82 individuals with SOX11
    variants had been reported in the literature as of the 2024 review.
    Ascertainment is genotype-first (research exome/genome cohorts and
    GeneMatcher), so case counts are not a population rate. The Orphanet figure
    for Coffin-Siris syndrome as an umbrella (ORPHA:1465) is deliberately NOT
    imported, because it would substantially over-estimate the SOX11 entity.
  evidence:
  - reference: PMID:37558216
    reference_title: "Pathogenic variants in SOX11 mimicking Pitt-Hopkins syndrome phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "32 out of 82 subjects reported in the literature with SOX11 variants"
    explanation: >-
      Establishes the cumulative published case count as of 2024. This is a
      literature tally, not a population rate, hence measure_type
      CASES_IN_LITERATURE and prevalence_class NOT_YET_DOCUMENTED.
- population: Coffin-Siris syndrome / BAF-disorder registry cohort
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    Denominator anchor rather than a population rate: SOX11 accounts for 10 of
    284 molecularly confirmed individuals in a Coffin-Siris/BAF registry, making
    it one of the rarest causes among the Coffin-Siris-spectrum genes and far
    behind ARID1B. This is the quantitative basis for not importing
    Coffin-Siris cohort statistics into this entry.
  evidence:
  - reference: PMID:24886874
    reference_title: "De novo SOX11 mutations cause Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SOX11 mutations appear to be a rare cause of CSS as only 2 out of 92 patients (2.2%) showed SOX11 abnormality"
    explanation: >-
      Independent quantification of the small SOX11 share of Coffin-Siris
      cohorts (2/92) in the original gene-discovery cohort.
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A mechanism-defined, multisystem Mendelian disorder of a developmental
      transcription factor. The dominant burden is neurodevelopmental, but the
      entry also spans endocrine (hypogonadotropic hypogonadism, pituitary),
      ocular, auditory, and skeletal manifestations, so the cross-organ
      genetics chapter is a better fit than a single organ-system chapter.
inheritance:
- name: Autosomal dominant SOX11 haploinsufficiency
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  expressivity: VARIABLE
  de_novo_rate: >-
    Most reported pathogenic SOX11 variants are de novo; in a systematic review
    of SOX11-related hypogonadotropic hypogonadism, 15 of 18 variants with
    parental testing were proven de novo. Rare transmission from a mildly
    affected parent has been documented.
  description: >-
    Heterozygous loss of SOX11 function (intragenic point variants or whole-gene
    2p25.2 deletion) is sufficient to cause disease, indicating that the
    paralogous SoxC factors SOX4 and SOX12 cannot compensate for reduced SOX11
    dosage in human neurodevelopment.
  evidence:
  - reference: PMID:42168980
    reference_title: "A de novo SOX11 mutation causing hypogonadotropic hypogonadism: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thirty unique variants were identified, 17/30 clustering within the HMG domain and 15/18 proven de-novo."
    explanation: >-
      Quantifies the predominance of de novo origin and the clustering of
      pathogenic variants in the HMG DNA-binding domain.
  - reference: PMID:33785884
    reference_title: "Maternal transmission of a mild Coffin-Siris syndrome phenotype caused by a SOX11 missense variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Maternal transmission of a mild Coffin-Siris syndrome phenotype caused by a SOX11 missense variant."
    explanation: >-
      Documents that a pathogenic SOX11 missense variant can be inherited from a
      mildly affected mother, so de novo occurrence is usual but not obligatory.
pathophysiology:
- name: Heterozygous SOX11 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    De novo missense variants clustering in the high-mobility-group (HMG)
    DNA-binding domain, truncating variants, or 2p25.2 microdeletions remove one
    functional copy of the single-exon SOX11 gene. Missense changes in the HMG
    domain either destabilise domain folding or distort the DNA-recognition
    loops.
  genes:
  - preferred_term: SOX11
    term:
      id: hgnc:11191
      label: SOX11
  molecular_functions:
  - preferred_term: sequence-specific DNA binding by the HMG box
    term:
      id: GO:0043565
      label: sequence-specific DNA binding
    modifier: DECREASED
  downstream:
  - target: Reduced Functional SOX11 Protein Dosage
    description: >-
      Deletion removes one copy outright; truncating variants remove the
      C-terminal transactivation domain; HMG-domain missense variants leave a
      nuclear-localised but DNA-binding-incompetent protein.
  evidence:
  - reference: PMID:24886874
    reference_title: "De novo SOX11 mutations cause Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we perform whole-exome sequencing in additional CSS patients, identifying de novo SOX11 mutations in two patients with a mild CSS phenotype."
    explanation: >-
      First identification of de novo SOX11 variants as a cause of this
      neurodevelopmental phenotype.
  - reference: PMID:24886874
    reference_title: "De novo SOX11 mutations cause Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "The two heterozygous mutations localize to the high-mobility group (HMG) domain."
    explanation: >-
      Localises the causal missense changes to the DNA-binding domain; FoldX
      modelling in the same paper predicts destabilisation (S60P) or altered
      DNA-recognition-loop conformation (Y116C).
  - reference: PMID:26543203
    reference_title: "Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified seven individuals with chromosome 2p25 deletions involving SOX11. Trio exome sequencing identified three de novo SOX11 variants, two missense (p.K50N; p.P120H) and one nonsense (p.C29*)."
    explanation: >-
      Establishes that whole-gene deletion and intragenic loss-of-function
      variants produce the same disorder, supporting haploinsufficiency.
  - reference: PMID:26543203
    reference_title: "Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The fact that both heterozygous deletions and mutations of SOX11 are associated with microcephaly suggests that loss of function and haploinsufficiency may be the underlying mechanism."
    explanation: >-
      States the haploinsufficiency mechanism explicitly on the basis of
      convergent deletion and point-variant phenotypes.
- name: Reduced Functional SOX11 Protein Dosage
  biological_scale: MOLECULAR
  description: >-
    Roughly half the normal amount of functional SOX11 activity remains. This is
    a pure dosage lesion, not a dominant-negative one: disease missense proteins
    still localise correctly to the nucleus, and the recurrent Y116C change
    behaves as a recessive loss of function when modelled at the orthologous
    residue in Caenorhabditis elegans. Critically, the paralogous SoxC factors
    SOX4 and SOX12 do not compensate in humans. SOX11 protein abundance is also
    set post-translationally by USP11-mediated deubiquitination, an independent
    route to functional SOX11 insufficiency.
  molecular_functions:
  - preferred_term: DNA-binding transcription factor activity
    term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: protein stabilization
    term:
      id: GO:0050821
      label: protein stabilization
    modifier: DECREASED
  downstream:
  - target: Impaired SOX11 Target Gene Transactivation
    description: >-
      Reduced functional SOX11 dosage lowers transactivation of SOX11 target
      genes at critical developmental windows.
  evidence:
  - reference: PMID:31035284
    reference_title: "A novel human stem cell model for Coffin-Siris syndrome-like syndrome reveals the importance of SOX11 dosage for neuronal differentiation and survival."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "demonstrating that in humans SOX11 haploinsufficiency cannot be compensated"
    explanation: >-
      Establishes that the SoxC paralogues SOX4 and SOX12 do not buffer reduced
      SOX11 dosage in humans, which is why heterozygous loss is pathogenic.
  - reference: PMID:40832700
    reference_title: "A Coffin-Siris syndrome-associated mutation modeled in Caenorhabditis elegans affects multiple developmental processes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "is a loss-of-function, recessive mutation that likely causes defects due to haploinsufficiency"
    explanation: >-
      The recurrent SOX11 Y116C change, modelled at the orthologous SEM-2 Y160
      residue, behaves as a recessive loss of function rather than a
      dominant-negative, supporting a pure dosage mechanism.
  - reference: PMID:35938035
    reference_title: "Identification and functional analysis of novel SOX11 variants in Chinese patients with Coffin-Siris syndrome 9."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "WT and two missense mutant SOX11 protein localized in the nucleus"
    explanation: >-
      Nuclear localisation is preserved for disease missense proteins, arguing
      against a trafficking defect or a sequestration/dominant-negative model
      and for a DNA-binding/transactivation dosage defect.
  - reference: PMID:33579706
    reference_title: "Usp11 controls cortical neurogenesis and neuronal migration through Sox11 stabilization."
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: "Usp11 ablation compromises Sox11 protein accumulation in the developing cortex, despite the induction of Sox11 mRNA."
    explanation: >-
      Shows that SOX11 protein abundance is controlled post-translationally by
      USP11, an independent route to functional SOX11 insufficiency. Marked
      PARTIAL because this is a separate USP11-related disorder, not a mechanism
      demonstrated in SOX11 variant carriers.
- name: Impaired SOX11 Target Gene Transactivation
  biological_scale: MOLECULAR
  description: >-
    SOX11 acts as a transcriptional activator at target promoters. Disease
    variants reduce SOX11-dependent transactivation in reporter assays, so the
    downstream neurodevelopmental gene programme is under-expressed at critical
    windows of brain development.
  molecular_functions:
  - preferred_term: DNA-binding transcription factor activity
    term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: regulation of transcription by RNA polymerase II
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    modifier: DECREASED
  downstream:
  - target: Neural Precursor Proliferation-Differentiation Imbalance
    description: >-
      Under-transactivation of neurogenic target genes shifts neural precursors
      away from timely neuronal differentiation.
  - target: Increased Neuronal Apoptosis
    description: >-
      Loss of SOX11-dependent survival signalling increases programmed death of
      newly generated neurons.
  - target: SOX11-Specific DNA Methylation Episignature
    description: >-
      Altered SOX11 transcriptional output is reflected in a reproducible
      genome-wide blood DNA methylation signature.
  - target: Elevated Hedgehog Signalling in the Developing Eye
    description: >-
      SOX11 normally restrains shha transcription; loss of that restraint
      raises Hedgehog pathway output during ocular morphogenesis.
  - target: Reduced FGF9-Driven Mandibular Mesenchyme Proliferation
    description: >-
      FGF9 is a direct SOX11 target driving proliferation in the developing
      mandible and palatal shelf.
  - target: Disrupted Nephrogenic Gdnf Domain Restriction
    description: >-
      SOX11 restricts the rostral extent of the Gdnf expression domain in the
      nephrogenic cord and regulates a protocadherin B cluster locus control
      region.
  - target: Impaired Hypothalamic-Pituitary Gonadotropic Axis Development
    description: >-
      Reduced SOX11 activity impairs development of the GnRH neuroendocrine
      axis and associated olfactory/pituitary structures.
  - target: Impaired Cochlear Nerve Development
    description: >-
      SOX11 is required for cochlear sensory neuron survival and axonal growth,
      so reduced activity can produce cochlear nerve deficiency.
  evidence:
  - reference: PMID:24886874
    reference_title: "De novo SOX11 mutations cause Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Luciferase assays using the GDF5 promoter in HeLa and ATDC5 cells, showed both mutant proteins had decreased transcriptional activities compared with wild type"
    explanation: >-
      Directly demonstrates that the disease-associated HMG-domain missense
      proteins are transcriptionally hypomorphic.
  - reference: PMID:26543203
    reference_title: "Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our luciferase reporter gene assays provide further evidence in support of this as they indicate a reduced ability of mutant SOX11 to induce gene expression."
    explanation: >-
      Independent replication of reduced transactivation for a second set of
      patient variants.
  - reference: PMID:32574812
    reference_title: "Regulatory roles for SOX11 in development, stem cells and cancer."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SOX11 regulates progenitor and stem cell behavior, and often acts together with the other two SOXC group members, SOX4 and SOX12, in regulating developmental processes, including neurogenesis and skeletogenesis."
    explanation: >-
      Review context for the developmental gene programme that SOX11 normally
      transactivates.
- name: Neural Precursor Proliferation-Differentiation Imbalance
  biological_scale: CELLULAR
  description: >-
    SOX11 haploinsufficiency shifts the balance between neural precursor
    proliferation and neuronal differentiation, so fewer neurons are generated
    per progenitor pool.
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  biological_processes:
  - preferred_term: neuron differentiation
    term:
      id: GO:0030182
      label: neuron differentiation
    modifier: DECREASED
  - preferred_term: cell population proliferation
    term:
      id: GO:0008283
      label: cell population proliferation
    modifier: DYSREGULATED
  downstream:
  - target: Reduced Cortical Neurogenesis and Brain Growth
    description: >-
      Fewer neurons are produced from the precursor pool, reducing cortical
      neuron output.
  evidence:
  - reference: PMID:31035284
    reference_title: "A novel human stem cell model for Coffin-Siris syndrome-like syndrome reveals the importance of SOX11 dosage for neuronal differentiation and survival."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "SOX11 haploinsufficiency impaired the generation of neurons and resulted in a proliferation/differentiation imbalance of neural precursor cells and enhanced neuronal cell death."
    explanation: >-
      Isogenic CRISPR/Cas9 SOX11+/- human embryonic stem cell model shows that
      one-copy loss alone is sufficient to produce this cellular phenotype.
- name: Increased Neuronal Apoptosis
  biological_scale: CELLULAR
  description: >-
    SOX11 also acts as a neuronal survival factor; reduced dosage increases
    apoptotic death of newly born neurons in the developing central nervous
    system.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: positive regulation of neuron apoptotic process
    term:
      id: GO:0043525
      label: positive regulation of neuron apoptotic process
    modifier: INCREASED
  downstream:
  - target: Reduced Cortical Neurogenesis and Brain Growth
    description: >-
      Loss of newly generated neurons compounds the reduced neuronal output and
      limits brain growth.
  evidence:
  - reference: PMID:31035284
    reference_title: "A novel human stem cell model for Coffin-Siris syndrome-like syndrome reveals the importance of SOX11 dosage for neuronal differentiation and survival."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "SOX11 haploinsufficiency impaired the generation of neurons and resulted in a proliferation/differentiation imbalance of neural precursor cells and enhanced neuronal cell death."
    explanation: >-
      The same isogenic human stem cell model demonstrates enhanced neuronal
      death on loss of a single SOX11 copy.
  - reference: PMID:24886874
    reference_title: "De novo SOX11 mutations cause Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "apoptotic increases exclusively in microcephalic embryos"
    explanation: >-
      Acridine orange and TUNEL staining in sox11a/b zebrafish morphants link
      increased CNS apoptosis to the small-head phenotype.
  - reference: PMID:26543203
    reference_title: "Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Sox11 knockdown does not alter proliferation but is associated with increased neuronal apoptosis"
    explanation: >-
      Independent amphibian evidence that Sox11 loss acts predominantly through
      neuronal survival rather than proliferation in that context.
- name: Reduced Cortical Neurogenesis and Brain Growth
  biological_scale: TISSUE
  description: >-
    The combination of impaired neuronal generation and increased neuronal death
    reduces the number of cortical neurons produced during fetal development,
    yielding a smaller brain with a thin cerebral cortex.
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  biological_processes:
  - preferred_term: neurogenesis
    term:
      id: GO:0022008
      label: neurogenesis
    modifier: DECREASED
  - preferred_term: cerebral cortex development
    term:
      id: GO:0021987
      label: cerebral cortex development
    modifier: DECREASED
  downstream:
  - target: Microcephaly and Impaired Cognitive Development
    description: >-
      Reduced cortical neuron number manifests postnatally as microcephaly,
      developmental delay, and intellectual disability.
  evidence:
  - reference: PMID:26543203
    reference_title: "Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "SOX11 null mice have reduced cortical neurogenesis secondary to reduced proliferation and abnormal differentiation of neuronal progenitor cells.3 This results in SOX11 null mice having reduced brain weights and thin cerebral cortices."
    explanation: >-
      Mouse data establishing the tissue-level consequence of Sox11 loss on
      cortical neurogenesis and brain size.
  - reference: PMID:26543203
    reference_title: "Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Morphants had significant reduction in head size compared with controls. This suggests that SOX11 loss of function can be associated with microcephaly."
    explanation: >-
      Xenopus Sox11 knockdown reproduces reduced head size, linking the
      molecular lesion to the brain-growth phenotype.
- name: Microcephaly and Impaired Cognitive Development
  biological_scale: ORGANISM
  description: >-
    The clinical endpoint of the neural arm of the cascade: postnatal
    microcephaly with global developmental delay, intellectual disability, and
    a high burden of autistic traits.
  evidence:
  - reference: PMID:26543203
    reference_title: "Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These individuals had microcephaly, developmental delay and shared dysmorphic features compatible with mild Coffin-Siris syndrome."
    explanation: >-
      Human cohort observation of the microcephaly/developmental-delay endpoint
      in SOX11 deletion and point-variant carriers.
  - reference: PMID:37558216
    reference_title: "Pathogenic variants in SOX11 mimicking Pitt-Hopkins syndrome phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we made a confirmation that overall SOX11 abnormalities feature a distinctive disorder characterised by severe ID, high incidence of microcephaly and low frequency of congenital malformations"
    explanation: >-
      Literature review of 32 well-characterised individuals confirming that
      severe intellectual disability plus microcephaly dominates the phenotype.
- name: SOX11-Specific DNA Methylation Episignature
  biological_scale: MOLECULAR
  description: >-
    Individuals with pathogenic SOX11 variants carry a reproducible,
    disorder-specific genome-wide blood DNA methylation pattern. This
    episignature is mechanistically informative as well as diagnostically
    useful: it separates SOX11 syndrome from the BAF (SWI/SNF) chromatin
    remodeller disorders with which SOX11 is clinically lumped.
  evidence:
  - reference: PMID:35341651
    reference_title: "SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A distinctive pattern of blood DNA methylation was identified in SOX11 syndrome, separating SOX11 syndrome from other BAFopathies."
    explanation: >-
      Direct molecular evidence that the SOX11 entity is separable from the
      BAFopathies, supporting a split rather than a lump against classical
      Coffin-Siris syndrome.
- name: Disrupted Ocular Morphogenesis
  biological_scale: TISSUE
  description: >-
    SOX11 is required for normal eye development. Reduced SOX11 activity can
    produce structural eye malformations (microphthalmia, iris coloboma) in a
    minority of affected individuals, which is why the OMIM/MONDO disease name
    carries the "with or without ocular malformations" qualifier.
  locations:
  - preferred_term: eye
    term:
      id: UBERON:0000970
      label: eye
  biological_processes:
  - preferred_term: eye development
    term:
      id: GO:0001654
      label: eye development
    modifier: DECREASED
  evidence:
  - reference: PMID:26543203
    reference_title: "Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "There is also evidence that SOX11 plays a role in ocular development. Sox11 knockdown in zebrafish induces microphthalmia with or without iris coloboma."
    explanation: >-
      Model-organism basis for the ocular arm of the SOX11 phenotype.
  - reference: PMID:26543203
    reference_title: "Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ocular abnormalities were present in both deletion and mutation cases; case 1 had right microphthalmia"
    explanation: >-
      Human observation of structural microphthalmia in a SOX11-only deletion
      carrier, matching the animal-model prediction.
- name: Impaired Hypothalamic-Pituitary Gonadotropic Axis Development
  biological_scale: TISSUE
  description: >-
    A subset of affected individuals have idiopathic hypogonadotropic
    hypogonadism, with anosmic (Kallmann-like) and normosmic forms, plus
    additional anterior pituitary hormone deficiencies and structural
    hypothalamic/pituitary and olfactory-bulb defects. This indicates that
    SOX11 is required for development of the GnRH neuroendocrine axis at both
    hypothalamic and pituitary levels.
  cell_types:
  - preferred_term: hypothalamic gonadotropin-releasing hormone neuron
    term:
      id: CL:0011111
      label: hypothalamic gonadotropin-releasing hormone neuron
  locations:
  - preferred_term: hypothalamus
    term:
      id: UBERON:0001898
      label: hypothalamus
  biological_processes:
  - preferred_term: hypothalamus development
    term:
      id: GO:0021854
      label: hypothalamus development
    modifier: DECREASED
  evidence:
  - reference: PMID:35341651
    reference_title: "SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Idiopathic hypogonadotropic hypogonadism was confirmed as a feature of SOX11 syndrome."
    explanation: >-
      Establishes hypogonadotropic hypogonadism as a bona fide feature of the
      SOX11 entity in a 38-patient cohort.
  - reference: PMID:39290158
    reference_title: "Expanding the Spectrum of Endocrine Abnormalities Associated With SOX11-related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deleterious SOX11 variants cause IHH and other pituitary hormone deficiencies, suggesting that the human SOX11-associated disorder may stem from both hypothalamic and pituitary level defects."
    explanation: >-
      Localises the endocrine lesion to both hypothalamic and pituitary levels
      based on a 1810-proband IHH cohort.
- name: Impaired Cochlear Nerve Development
  biological_scale: TISSUE
  description: >-
    SOX11 is highly expressed in the developing inner ear and is required for
    sensory neuron survival and axonal outgrowth. Reduced dosage can produce
    cochlear nerve hypoplasia or aplasia with sensorineural hearing loss despite
    grossly normal inner ear structures.
  locations:
  - preferred_term: cochlear nerve
    term:
      id: UBERON:0004727
      label: cochlear nerve
  evidence:
  - reference: PMID:35642566
    reference_title: "Cochlear nerve deficiency in SOX11-related Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Homozygous ablation of SOX11 in a mouse model resulted in a reduction in sensory neuron survival and decreased axonal growth. A heterozygous knockout mice model had hearing impairment with grossly normal inner ear structures like the two probands reported."
    explanation: >-
      Mouse data connect SOX11 dosage to sensory neuron survival and hearing
      impairment with structurally normal inner ears.
  - reference: PMID:35642566
    reference_title: "Cochlear nerve deficiency in SOX11-related Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They have unilateral sensorineural hearing loss due to cochlear nerve deficiency confirmed on MRI."
    explanation: >-
      Human imaging confirmation of cochlear nerve deficiency in two unrelated
      SOX11 probands.
- name: Elevated Hedgehog Signalling in the Developing Eye
  biological_scale: CELLULAR
  description: >-
    A mechanistically counter-intuitive arm: loss of SOX11 raises rather than
    lowers signalling output downstream, because SOX11 normally acts as a
    negative regulator of shha transcription during ocular morphogenesis. The
    resulting excess Hedgehog signalling causes failure of choroid fissure
    closure. In zebrafish the ocular phenotype is rescued by the Hedgehog
    inhibitor cyclopamine, so the lesion is pathway hyperactivity, not loss.
  biological_processes:
  - preferred_term: smoothened signaling pathway
    term:
      id: GO:0007224
      label: smoothened signaling pathway
    modifier: INCREASED
  locations:
  - preferred_term: eye
    term:
      id: UBERON:0000970
      label: eye
  downstream:
  - target: Disrupted Ocular Morphogenesis
    description: >-
      Excess Hedgehog signalling disrupts choroid fissure closure and lens
      development, producing coloboma and microphthalmia.
  evidence:
  - reference: PMID:25010521
    reference_title: "Sox11 is required to maintain proper levels of Hedgehog signaling during vertebrate ocular morphogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Sox11 Negatively Regulates Hedgehog Signaling"
    explanation: >-
      Establishes the direction of the effect: SOX11 restrains Hedgehog
      signalling, so SOX11 loss produces pathway hyperactivity in the eye.
- name: Reduced FGF9-Driven Mandibular Mesenchyme Proliferation
  biological_scale: CELLULAR
  description: >-
    SOX11 directly regulates Fgf9 expression, and Fgf9 in turn drives Cyclin
    D1-dependent proliferation of the developing mandibular mesenchyme. Loss of
    SOX11 reduces this proliferation.
  biological_processes:
  - preferred_term: cell population proliferation
    term:
      id: GO:0008283
      label: cell population proliferation
    modifier: DECREASED
  downstream:
  - target: Mandibular Hypoplasia with Secondary Palatal Shelf Obstruction
    description: >-
      Reduced mandibular mesenchyme proliferation produces mandibular
      hypoplasia.
  evidence:
  - reference: PMID:26826126
    reference_title: "Ablation of the Sox11 Gene Results in Clefting of the Secondary Palate Resembling the Pierre Robin Sequence."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We found that loss of Sox11led to reduced cell proliferation in the developing mandibular mesenchyme via Cyclin D1, leading to mandibular hypoplasia, which blocks tongue descent."
    explanation: >-
      Identifies the proliferative defect and its immediate anatomical
      consequence in the Sox11 mouse mutant.
  - reference: PMID:26826126
    reference_title: "Ablation of the Sox11 Gene Results in Clefting of the Secondary Palate Resembling the Pierre Robin Sequence."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we show, using in vitro assays, that Sox11 directly regulates the expression of Fgf9 and that application of FGF9 protein to Sox11-deficient palatal shelves restores the rate of BrdU incorporation."
    explanation: >-
      Establishes FGF9 as the direct SOX11 target mediating the proliferative
      arm, with rescue on FGF9 replacement.
- name: Mandibular Hypoplasia with Secondary Palatal Shelf Obstruction
  biological_scale: TISSUE
  description: >-
    The cleft palate seen in SOX11 deficiency is mechanistically secondary, not
    a primary palatal-shelf defect. The shelves themselves retain fusion and
    elevation competence; mandibular hypoplasia mispositions the tongue, which
    physically obstructs palatal shelf elevation. The resulting picture
    resembles the Pierre Robin sequence.
  biological_processes:
  - preferred_term: roof of mouth development
    term:
      id: GO:0060021
      label: roof of mouth development
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:26826126
    reference_title: "Ablation of the Sox11 Gene Results in Clefting of the Secondary Palate Resembling the Pierre Robin Sequence."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "As in the wild type, the palatal shelves in the Sox11 mutant undergo outgrowth in a downward direction and exhibit potential for fusion and elevation. However, mutant palatal shelves encounter clefting, which is associated with a malpositioned tongue that results in physical obstruction of palatal shelf elevation"
    explanation: >-
      Directly demonstrates that the clefting is obstructive and secondary
      rather than a primary defect of the palatal shelves.
- name: Disrupted Nephrogenic Gdnf Domain Restriction
  biological_scale: TISSUE
  description: >-
    SOX11 is expressed in both mesenchymal and epithelial components of the
    early kidney anlagen and restricts the rostral extent of the Gdnf expression
    domain in the nephrogenic cord. Loss of Sox11 extends that domain and
    produces duplex kidney; later, SOX11 is required in the intermediate nephron
    segment for elongation of Henle's loop.
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  biological_processes:
  - preferred_term: kidney development
    term:
      id: GO:0001822
      label: kidney development
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:29459093
    reference_title: "Sox11 gene disruption causes congenital anomalies of the kidney and urinary tract (CAKUT)."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Deletion of Sox11 in mice causes an extension of the domain expressing Gdnf within rostral regions of the nephrogenic cord and results in duplex kidney formation."
    explanation: >-
      Defines the developmental mechanism linking Sox11 loss to a structural
      kidney malformation.
  - reference: PMID:29459093
    reference_title: "Sox11 gene disruption causes congenital anomalies of the kidney and urinary tract (CAKUT)."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "mutation analysis in a cohort of patients suffering from CAKUT identified a series of rare SOX11 variants, one of which interferes with the transactivation capacity of the SOX11 protein"
    explanation: >-
      Human variant evidence linking SOX11 to CAKUT. Marked PARTIAL because
      these were rare variants in a CAKUT cohort rather than individuals with
      the full SOX11 neurodevelopmental syndrome.
phenotypes:
- name: Oculomotor Apraxia
  category: Ophthalmologic
  description: >-
    Cogan-type oculomotor apraxia (impaired initiation of voluntary horizontal
    saccades) is reported as a distinguishing feature of the SOX11 entity and is
    named in the MONDO definition of the SOX11 disorder. It is likely
    under-ascertained because it requires specialised neuro-ophthalmological
    assessment.
  phenotype_term:
    preferred_term: Oculomotor apraxia
    term:
      id: HP:0000657
      label: Oculomotor apraxia
  evidence:
  - reference: PMID:26543203
    reference_title: "Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cases 7 and 9 had oculomotor apraxia"
    explanation: >-
      Direct observation of oculomotor apraxia in two individuals in the 2p25
      deletion and de novo variant cohort.
  - reference: PMID:40933692
    reference_title: "Case Report: Observation of early-onset high myopia with fundus tessellation changes in Coffin-Siris syndrome 9 (CSS9) and literature review."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "the most prevalent phenotype was ocular motor disorder (15/58, 29.31%)"
    explanation: >-
      Systematic pooled review of 58 published SOX11 cases finds ocular motor
      disorder to be the most prevalent ophthalmological phenotype. Marked
      PARTIAL and no band assigned to this node: "ocular motor disorder" is a
      broader category than Cogan-type oculomotor apraxia specifically, so
      15/58 (29.31%) is an upper bound on the apraxia frequency rather than a
      denominator for it. The pooled ophthalmological figure is banded on the
      Ophthalmological Malformation entry instead.
- name: Ophthalmological Malformation
  category: Ophthalmologic
  description: >-
    Pooled ophthalmological involvement of any type - eyelid abnormalities,
    ocular motor disorders, ocular deformities, visual malfunctions and fundus
    changes - across the published SOX11 case literature. Curated as an umbrella
    entry because it is the only ocular finding with a denominator; the
    individual ocular phenotypes are curated separately below and unbanded.
  phenotype_term:
    preferred_term: Ophthalmological malformation
    term:
      id: HP:0000478
      label: Abnormality of the eye
  frequency: FREQUENT
  evidence:
  - reference: PMID:40933692
    reference_title: "Case Report: Observation of early-onset high myopia with fundus tessellation changes in Coffin-Siris syndrome 9 (CSS9) and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Quantitative analysis of the ophthalmological phenotypic spectrum of the 58 cases (including our proband) revealed that almost half (26/58, 44.83%) presented ophthalmological malformations"
    explanation: >-
      Systematic PRISMA-based review pooling 57 published SOX11 cases plus the
      authors' proband, restricted to single-nucleotide variants after excluding
      contiguous-gene CNV cases. 26/58 = 44.83%, which falls in the FREQUENT
      (30-79%) band. This is the first denominator-based ocular frequency for
      the disorder and is what the OMIM/MONDO "with or without ocular
      malformation" qualifier had previously left unquantified.
- name: Delayed Puberty
  category: Endocrine
  description: >-
    Delayed or absent puberty is the principal presenting manifestation of the
    endocrine arm in both sexes. Males may additionally present at birth with
    genital malformations, so females are typically ascertained later.
  phenotype_term:
    preferred_term: Delayed puberty
    term:
      id: HP:0000823
      label: Delayed puberty
  evidence:
  - reference: PMID:42168980
    reference_title: "A de novo SOX11 mutation causing hypogonadotropic hypogonadism: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a 13-year-old Chinese girl who presented with delayed puberty (Tanner B1, PH1), infantile uterus and low basal gonadotropins."
    explanation: >-
      Delayed puberty as the presenting feature of SOX11-related
      hypogonadotropic hypogonadism.
- name: Renal and Urinary Tract Anomalies
  category: Genitourinary
  description: >-
    Structural kidney anomalies (small kidney, malrotation, duplex kidney) are
    the most commonly reported internal organ malformation. The developmental
    basis is a Sox11-dependent restriction of the nephrogenic Gdnf domain.
  phenotype_term:
    preferred_term: Abnormality of the kidney
    term:
      id: HP:0000077
      label: Abnormality of the kidney
  evidence:
  - reference: PMID:24886874
    reference_title: "De novo SOX11 mutations cause Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Abdominal echography showed her left kidney was slightly small in size."
    explanation: >-
      Renal anomaly in the first index SOX11 proband.
  - reference: PMID:29459093
    reference_title: "Sox11 gene disruption causes congenital anomalies of the kidney and urinary tract (CAKUT)."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here we show that the transcription factor SOX11 is a crucial regulator of kidney development."
    explanation: >-
      Mechanistic support for a genuine SOX11-dependent renal developmental
      role underlying the human anomalies.
- name: Coloboma
  category: Ophthalmologic
  description: >-
    Coloboma, arising from failure of choroid fissure closure, is one of the
    structural ocular malformations named in the disease definition and is
    reproduced by sox11 loss in zebrafish through excess Hedgehog signalling.
  phenotype_term:
    preferred_term: Coloboma
    term:
      id: HP:0000589
      label: Coloboma
  evidence:
  - reference: PMID:26543203
    reference_title: "Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Sox11 knockdown in zebrafish induces microphthalmia with or without iris coloboma."
    explanation: >-
      Model-organism evidence for the coloboma arm. Human coloboma in SOX11
      carriers is documented in the larger cohort but not in a quotable
      abstract, so no frequency band is assigned.
  - reference: PMID:25010521
    reference_title: "Sox11 is required to maintain proper levels of Hedgehog signaling during vertebrate ocular morphogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Sox11 Negatively Regulates Hedgehog Signaling"
    explanation: >-
      Provides the mechanism (Hedgehog de-repression) by which SOX11 loss
      produces failure of choroid fissure closure.
- name: Global Developmental Delay
  category: Neurologic
  description: >-
    Delayed acquisition of motor, language, and adaptive milestones, reported in
    essentially every published individual with a pathogenic SOX11 variant.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:39333428
    reference_title: "Novel variants in the SOX11 gene: clinical description of seven new patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main clinical features included neurodevelopmental delay (7/7) and intellectual disability (5/7), autism/attention deficit hyperactivity disorder (5/7), microcephaly (4/7), short stature (4/7), hypotonia (4/7), and clinodactyly of the 5th fingers (5/7)."
    explanation: >-
      Neurodevelopmental delay in 7/7 (100%) of this consecutive case series
      supports the VERY_FREQUENT band; the cohort is small (n=7), so the band is
      corroborated by the qualitative statements in PMID:26543203 that all
      deletion and point-variant carriers had developmental delay.
  - reference: PMID:35938035
    reference_title: "Identification and functional analysis of novel SOX11 variants in Chinese patients with Coffin-Siris syndrome 9."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DD − + + 36/37"
    explanation: >-
      Table 1 pools the published SOX11 literature (n = 58 reported patients)
      and gives developmental delay in 36/37 individuals for whom it was
      reported. 36/37 = 97%, confirming the VERY_FREQUENT (80-99%) band on a
      denominator five times larger than the n=7 series above.
- name: Intellectual Disability
  category: Neurologic
  description: >-
    Intellectual disability of variable severity. Early reports emphasised a
    mild end of the spectrum, but subsequent larger literature reviews describe
    severe intellectual disability as characteristic.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:35938035
    reference_title: "Identification and functional analysis of novel SOX11 variants in Chinese patients with Coffin-Siris syndrome 9."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ID N/R + + 38/40"
    explanation: >-
      Table 1 of this report pools the published SOX11 literature (n = 58
      reported patients) and gives intellectual disability in 38/40 individuals
      for whom cognition was reported. 38/40 = 95%, which falls in the
      VERY_FREQUENT (80-99%) band. This pooled denominator supersedes the n=7
      series below for band assignment.
  - reference: PMID:39333428
    reference_title: "Novel variants in the SOX11 gene: clinical description of seven new patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main clinical features included neurodevelopmental delay (7/7) and intellectual disability (5/7)"
    explanation: >-
      Intellectual disability in 5/7 (71%) of this small consecutive series.
      Retained as corroborating evidence only; the band is set from the pooled
      38/40 denominator above rather than from this n=7 figure.
  - reference: PMID:37558216
    reference_title: "Pathogenic variants in SOX11 mimicking Pitt-Hopkins syndrome phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SOX11 abnormalities feature a distinctive disorder characterised by severe ID, high incidence of microcephaly and low frequency of congenital malformations"
    explanation: >-
      Review of 32 detailed published cases characterising the severity of the
      cognitive phenotype.
- name: Microcephaly
  category: Neurologic
  description: >-
    Reduced occipitofrontal head circumference, usually postnatal, reflecting
    reduced cortical neurogenesis. Microcephaly is one of the two features named
    in the OMIM/MONDO disease label.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  frequency: FREQUENT
  evidence:
  - reference: PMID:39333428
    reference_title: "Novel variants in the SOX11 gene: clinical description of seven new patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "microcephaly (4/7), short stature (4/7), hypotonia (4/7), and clinodactyly of the 5th fingers (5/7)"
    explanation: >-
      Microcephaly in 4/7 (57%) maps to the FREQUENT (30-79%) band.
  - reference: PMID:26543203
    reference_title: "Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Microcephaly was reported in all but two."
    explanation: >-
      In the seven 2p25 deletion carriers, microcephaly was present in five of
      seven, consistent with the FREQUENT band.
  - reference: PMID:35938035
    reference_title: "Identification and functional analysis of novel SOX11 variants in Chinese patients with Coffin-Siris syndrome 9."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Microcephaly −− + 11/28"
    explanation: >-
      Table 1 pools the published SOX11 literature (n = 58 reported patients)
      and gives microcephaly in 11/28 individuals with a reported head
      circumference. 11/28 = 39%, which confirms the FREQUENT (30-79%) band on a
      four-fold larger denominator than the n=7 series above.
- name: Cerebellar Vermis Hypoplasia
  category: Neurologic
  description: >-
    Structural cerebellar anomaly on brain MRI. Reported in an individual whose
    only detected lesion was a de novo SOX11 nonsense variant with a normal
    array CGH, so the finding is attributable to SOX11 rather than to a
    contiguous-gene 2p25 deletion. Brain imaging is performed in a minority of
    published cases, so the structural CNS phenotype is under-ascertained.
  phenotype_term:
    preferred_term: Cerebellar vermis hypoplasia
    term:
      id: HP:0001320
      label: Cerebellar vermis hypoplasia
  evidence:
  - reference: PMID:26543203
    reference_title: "Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A brain MRI detected hypoplasia of the inferior aspect of the cerebellar vermis. Array CGH (180k, Agilent) was normal. Exome sequencing identified a de novo, nonsense variant in SOX11"
    explanation: >-
      Case 10 of this series: cerebellar vermis hypoplasia in an individual with
      a normal array CGH and an isolated de novo SOX11 nonsense variant. No
      frequency band is assigned - this is a single reported individual and no
      denominator for imaged SOX11 patients is available in a quotable source.
- name: Autistic Behavior
  category: Behavioral
  description: >-
    Clinically significant autistic traits are near-universal on standardised
    assessment, though social motivation is a relative strength.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:37924570
    reference_title: "Short report: Behavioural characterisation of SOX11 syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most (90 %) were found to exhibit clinically relevant levels of autistic traits, with 62 % scoring in the \"severe\" range, though social motivation was observed to be a relative strength in the cohort overall."
    explanation: >-
      Standardised SRS-2 assessment of 21 individuals gives a direct
      quantitative frequency of 90%, in the VERY_FREQUENT (80-99%) band.
- name: Impaired Adaptive Behaviour
  category: Behavioral
  description: >-
    Borderline-to-mild impairment of adaptive behaviour on the Vineland
    Adaptive Behaviour Scales, with communication and daily living skills more
    affected than socialisation.
  phenotype_term:
    preferred_term: Impaired adaptive behaviour (Vineland composite)
  evidence:
  - reference: PMID:37924570
    reference_title: "Short report: Behavioural characterisation of SOX11 syndrome."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Most were found to have borderline (33 %) or mild (39 %) impairment in adaptive behaviour, with more difficulties in communication and daily living than socialisation in the cohort overall."
    explanation: >-
      Supports the adaptive-behaviour profile. Marked PARTIAL because the HPO
      term for borderline intellectual functioning is an imperfect proxy for the
      Vineland adaptive-behaviour construct actually measured.
- name: Attention Deficit Hyperactivity Disorder
  category: Behavioral
  description: >-
    Attention deficit and hyperactivity are commonly reported, frequently
    alongside autistic traits.
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:39333428
    reference_title: "Novel variants in the SOX11 gene: clinical description of seven new patients."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "autism/attention deficit hyperactivity disorder (5/7)"
    explanation: >-
      Supports the association, but the source counts autism and ADHD together,
      so no separate ADHD frequency band can be assigned.
- name: Hypotonia
  category: Neurologic
  description: Generalised hypotonia, often present from the neonatal period.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  frequency: FREQUENT
  evidence:
  - reference: PMID:39333428
    reference_title: "Novel variants in the SOX11 gene: clinical description of seven new patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "microcephaly (4/7), short stature (4/7), hypotonia (4/7), and clinodactyly of the 5th fingers (5/7)"
    explanation: >-
      Hypotonia in 4/7 (57%) maps to the FREQUENT (30-79%) band.
- name: Feeding Difficulties
  category: Digestive
  description: >-
    Neonatal and infantile feeding difficulties, typically associated with
    hypotonia.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:26543203
    reference_title: "Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Microcephaly, low birth weight and neonatal feeding difficulties associated with hypotonia were frequent findings."
    explanation: >-
      Describes neonatal feeding difficulty as a frequent finding among
      individuals with de novo SOX11 variants.
- name: Expressive Language Delay
  category: Neurologic
  description: >-
    Speech and expressive language are disproportionately affected relative to
    other domains.
  phenotype_term:
    preferred_term: Expressive language delay
    term:
      id: HP:0002474
      label: Expressive language delay
  evidence:
  - reference: PMID:26543203
    reference_title: "Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All had developmental delay, with particularly marked speech delay."
    explanation: >-
      Identifies speech delay as a disproportionately affected domain in the
      2p25 deletion cohort.
- name: Short Stature
  category: Growth
  description: >-
    Proportionate short stature and general growth deficiency, sometimes with
    low birth weight.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  frequency: FREQUENT
  evidence:
  - reference: PMID:39333428
    reference_title: "Novel variants in the SOX11 gene: clinical description of seven new patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "microcephaly (4/7), short stature (4/7), hypotonia (4/7)"
    explanation: >-
      Short stature in 4/7 (57%) maps to the FREQUENT (30-79%) band.
  - reference: PMID:35938035
    reference_title: "Identification and functional analysis of novel SOX11 variants in Chinese patients with Coffin-Siris syndrome 9."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Short stature + − + 10/30"
    explanation: >-
      Table 1 pools the published SOX11 literature (n = 58 reported patients)
      and gives short stature in 10/30 individuals with a reported height.
      10/30 = 33%, confirming the FREQUENT (30-79%) band on a four-fold larger
      denominator than the n=7 series above.
- name: Growth Delay
  category: Growth
  description: >-
    Overall growth deficiency, part of the original clinical description of the
    SOX11 phenotype.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:35642566
    reference_title: "Cochlear nerve deficiency in SOX11-related Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "phenotypic manifestations of CSS including global developmental delay, growth deficiency, and hypoplastic nails"
    explanation: >-
      Growth deficiency reported as a manifestation in two SOX11 probands.
- name: Clinodactyly of the 5th Finger
  category: Musculoskeletal
  description: >-
    Incurving of the fifth finger, one of the mild distal-limb findings that
    prompted the original Coffin-Siris-like classification.
  phenotype_term:
    preferred_term: Clinodactyly of the 5th finger
    term:
      id: HP:0004209
      label: Clinodactyly of the 5th finger
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:35938035
    reference_title: "Identification and functional analysis of novel SOX11 variants in Chinese patients with Coffin-Siris syndrome 9."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinodactyly 5th ﬁnger −− 10/55"
    explanation: >-
      Table 1 pools the published SOX11 literature (n = 58 reported patients)
      and gives fifth-finger clinodactyly in 10/55. 10/55 = 18%, which falls in
      the OCCASIONAL (5-29%) band. This pooled denominator, not the n=7 series
      below, governs the band: the 5/7 (71%) figure is an outlier from a small
      consecutive series.
  - reference: PMID:39333428
    reference_title: "Novel variants in the SOX11 gene: clinical description of seven new patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and clinodactyly of the 5th fingers (5/7)"
    explanation: >-
      Fifth-finger clinodactyly in 5/7 of this seven-patient series. Retained as
      a direct observation; it is not used for the band because the pooled
      55-patient denominator above is eight times larger.
- name: Hypoplastic Fifth Fingernail
  category: Integument
  description: >-
    Hypoplasia of the nail and/or distal phalanx of the fifth digit, a hallmark
    of the Coffin-Siris-like presentation.
  phenotype_term:
    preferred_term: Hypoplastic fifth fingernail
    term:
      id: HP:0008398
      label: Hypoplastic fifth fingernail
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:35938035
    reference_title: "Identification and functional analysis of novel SOX11 variants in Chinese patients with Coffin-Siris syndrome 9."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypoplastic nails −− − 6/55"
    explanation: >-
      Table 1 pools the published SOX11 literature (n = 58 reported patients)
      and gives hypoplastic nails in 6/55. 6/55 = 11%, which falls in the
      OCCASIONAL (5-29%) band. The pooled row is for hypoplastic nails
      generally; in this disorder the reported nail hypoplasia is
      overwhelmingly fifth-digit, which is how it is curated here.
  - reference: PMID:26543203
    reference_title: "Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypoplasia of the distal phalanx of the fifth finger, broad halluces,"
    explanation: >-
      Documents fifth-digit distal phalanx and nail hypoplasia among individuals
      with de novo SOX11 variants.
- name: Hypertrichosis
  category: Integument
  description: >-
    Increased body hair, one of the shared dysmorphic features noted in the
    first two SOX11 probands.
  phenotype_term:
    preferred_term: Hypertrichosis
    term:
      id: HP:0000998
      label: Hypertrichosis
  evidence:
  - reference: PMID:24886874
    reference_title: "De novo SOX11 mutations cause Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "they do share features in common, namely, hypertrichosis, arched eyebrows, low-set ears, auricular back-rotationand full cheeks"
    explanation: >-
      Hypertrichosis listed among the features shared by the two index SOX11
      probands.
- name: Hypogonadotropic Hypogonadism
  category: Endocrine
  description: >-
    Idiopathic hypogonadotropic hypogonadism with delayed or absent puberty,
    presenting as primary amenorrhoea with prepubertal uterus in females and
    micropenis/cryptorchidism/small testes in males. Both anosmic
    (Kallmann-like) and normosmic forms occur. This is the second qualifying
    feature in the OMIM/MONDO disease label.
  phenotype_term:
    preferred_term: Hypogonadotropic hypogonadism
    term:
      id: HP:0000044
      label: Hypogonadotropic hypogonadism
  evidence:
  - reference: PMID:35341651
    reference_title: "SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Idiopathic hypogonadotropic hypogonadism was confirmed as a feature of SOX11 syndrome."
    explanation: >-
      Confirms hypogonadotropic hypogonadism as an established feature in the
      largest deep-phenotyped SOX11 cohort. No frequency band is assigned
      because the abstract does not report a denominator.
  - reference: PMID:39333428
    reference_title: "Novel variants in the SOX11 gene: clinical description of seven new patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HH was confirmed in two female patients with primary amenorrhea, nonvisualized/prepubertal size of the uterus, and nonvisualized ovaries."
    explanation: >-
      Independent confirmation with explicit endocrine and imaging criteria.
- name: Primary Amenorrhea
  category: Genitourinary
  description: >-
    Absent menarche in affected females, the usual presenting sign of
    hypogonadotropic hypogonadism in this disorder.
  phenotype_term:
    preferred_term: Primary amenorrhea
    term:
      id: HP:0000786
      label: Primary amenorrhea
  evidence:
  - reference: PMID:39333428
    reference_title: "Novel variants in the SOX11 gene: clinical description of seven new patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HH was confirmed in two female patients with primary amenorrhea, nonvisualized/prepubertal size of the uterus, and nonvisualized ovaries."
    explanation: >-
      Direct report of primary amenorrhoea in two affected females.
- name: Micropenis
  category: Genitourinary
  description: Undervirilisation in affected males, suggestive of hypogonadotropic hypogonadism.
  phenotype_term:
    preferred_term: Micropenis
    term:
      id: HP:0000054
      label: Micropenis
  evidence:
  - reference: PMID:39333428
    reference_title: "Novel variants in the SOX11 gene: clinical description of seven new patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two of the male patients presented with micropenis, two had cryptorchidism, and one had decreased testicular size, which are suggestive findings of HH."
    explanation: >-
      Direct report of micropenis in two affected males.
- name: Cryptorchidism
  category: Genitourinary
  description: Undescended testes, reported alongside other signs of undervirilisation.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:39333428
    reference_title: "Novel variants in the SOX11 gene: clinical description of seven new patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two of the male patients presented with micropenis, two had cryptorchidism, and one had decreased testicular size, which are suggestive findings of HH."
    explanation: >-
      Direct report of cryptorchidism in two affected males.
  - reference: PMID:35938035
    reference_title: "Identification and functional analysis of novel SOX11 variants in Chinese patients with Coffin-Siris syndrome 9."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cryptorchidism + N/A + 5/6"
    explanation: >-
      Table 1 pools the published SOX11 literature and gives cryptorchidism in
      5/6. No frequency band is assigned: the denominator of 6 is the subset of
      the 28 reported males in whom genital examination was documented, so 5/6
      is a reporting-conditional figure rather than a cohort frequency, and
      converting it to a band would overstate what the table supports.
- name: Anosmia
  category: Neurologic
  description: >-
    Impaired olfaction defines the Kallmann-like (anosmic) subset of
    SOX11-related hypogonadotropic hypogonadism.
  phenotype_term:
    preferred_term: Anosmia
    term:
      id: HP:0000458
      label: Anosmia
  evidence:
  - reference: PMID:39290158
    reference_title: "Expanding the Spectrum of Endocrine Abnormalities Associated With SOX11-related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The phenotypic spectrum of SOX11 variant carriers revealed additional endocrine defects including anosmic and normosmic forms of IHH, GH deficiency, pituitary and hypothalamic structural defects, and hypothyroidism."
    explanation: >-
      Establishes that both anosmic and normosmic IHH occur in SOX11 variant
      carriers.
- name: Hypoplasia of the Olfactory Bulb
  category: Neurologic
  description: >-
    Olfactory bulb and nerve hypoplasia on MRI, fulfilling structural Kallmann
    syndrome criteria in a SOX11 proband.
  phenotype_term:
    preferred_term: Hypoplasia of the olfactory bulb
    term:
      id: HP:0040326
      label: Hypoplasia of the olfactory bulb
  evidence:
  - reference: PMID:42168980
    reference_title: "A de novo SOX11 mutation causing hypogonadotropic hypogonadism: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Olfactory and pituitary MRI revealed bilateral olfactory-bulb/nerve hypoplasia and a pituitary height of 3.4 mm, fulfilling Kallmann-syndrome criteria."
    explanation: >-
      Imaging documentation of olfactory bulb hypoplasia in a SOX11 variant
      carrier.
- name: Hypothyroidism
  category: Endocrine
  description: >-
    Part of the broader anterior pituitary hormone deficiency spectrum reported
    in SOX11 variant carriers.
  phenotype_term:
    preferred_term: Hypothyroidism
    term:
      id: HP:0000821
      label: Hypothyroidism
  evidence:
  - reference: PMID:39290158
    reference_title: "Expanding the Spectrum of Endocrine Abnormalities Associated With SOX11-related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "additional endocrine defects including anosmic and normosmic forms of IHH, GH deficiency, pituitary and hypothalamic structural defects, and hypothyroidism"
    explanation: >-
      Hypothyroidism listed among the endocrine defects in SOX11 variant
      carriers.
- name: Microphthalmia
  category: Ophthalmologic
  description: >-
    Structural reduction in eye size, part of the "ocular malformations"
    qualifier in the disease name. Infrequent.
  phenotype_term:
    preferred_term: Microphthalmia
    term:
      id: HP:0000568
      label: Microphthalmia
  evidence:
  - reference: PMID:26543203
    reference_title: "Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ocular abnormalities were present in both deletion and mutation cases; case 1 had right microphthalmia"
    explanation: >-
      Unilateral microphthalmia in a carrier of a deletion containing SOX11
      only, so the finding is attributable to SOX11 loss.
- name: Iris Coloboma
  category: Ophthalmologic
  description: >-
    Iris coloboma has been reported with SOX11 variants and is reproduced by
    sox11 knockdown in zebrafish.
  phenotype_term:
    preferred_term: Iris coloboma
    term:
      id: HP:0000612
      label: Iris coloboma
  evidence:
  - reference: PMID:26543203
    reference_title: "Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "variants in SOX11 have also been identified in two individuals with iris coloboma and no neurodevelopmental phenotype"
    explanation: >-
      Marked PARTIAL: the two individuals with iris coloboma had no
      neurodevelopmental phenotype and carried variants outside the HMG domain,
      so this may represent a distinct, milder allelic presentation rather than
      a feature of the full syndrome.
- name: Sensorineural Hearing Impairment
  category: Auditory
  description: >-
    Sensorineural hearing loss, in reported cases due to cochlear nerve
    deficiency or inner ear malformation rather than conductive pathology.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:36369738
    reference_title: "Two SOX11 variants cause Coffin-Siris syndrome with a new feature of sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deleterious SOX11 variants can result in sensorineural hearing loss with inner ear malformation, potentially extending the array of phenotypes associated with these pathogenic variants."
    explanation: >-
      Two Chinese probands with de novo SOX11 variants and syndromic
      sensorineural hearing loss.
  - reference: PMID:35642566
    reference_title: "Cochlear nerve deficiency in SOX11-related Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They have unilateral sensorineural hearing loss due to cochlear nerve deficiency confirmed on MRI."
    explanation: >-
      Independent report of sensorineural hearing loss with a defined
      cochlear-nerve mechanism.
- name: Cochlear Nerve Hypoplasia
  category: Auditory
  description: >-
    Absence or hypoplasia of the cochlear nerve on MRI, proposed as a new
    phenotypic feature of the SOX11 disorder.
  phenotype_term:
    preferred_term: Cochlear nerve hypoplasia
    term:
      id: HP:0034585
      label: Cochlear nerve hypoplasia
  evidence:
  - reference: PMID:35642566
    reference_title: "Cochlear nerve deficiency in SOX11-related Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We propose cochlear nerve deficiency as a new phenotypic feature of SOX11-related CSS."
    explanation: >-
      Explicit proposal of cochlear nerve deficiency as a SOX11-associated
      feature, based on two MRI-confirmed probands.
- name: Cleft Palate
  category: Craniofacial
  description: >-
    Cleft palate has been described in a single individual with a SOX11
    variant, implicating SOX11 in human palatogenesis.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:29437512
    reference_title: "Observation of Cleft Palate in an Individual with SOX11 Mutation: Indication of a Role for SOX11 in Human Palatogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This boy had a cleft palate, a feature not previously seen in other patients with SOX11 mutations."
    explanation: >-
      Single-case report; no frequency band is assigned because this is an
      isolated observation.
- name: Coarctation of Aorta
  category: Cardiovascular
  description: >-
    Congenital cardiac outflow anomaly reported in a single SOX11 proband;
    Sox11 has a documented role in murine cardiac outflow tract development.
  phenotype_term:
    preferred_term: Coarctation of aorta
    term:
      id: HP:0001680
      label: Coarctation of aorta
  evidence:
  - reference: PMID:28787104
    reference_title: "Coffin-Siris syndrome and cardiac anomaly with a novel SOX11 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He showed the CSS phenotype and coarctation of the aorta. Sox11 is known to be associated with cardiac outflow development in mouse studies."
    explanation: >-
      Single-case report; no frequency band is assigned. The mouse outflow-tract
      role provides mechanistic plausibility.
genetic:
- name: SOX11
  gene_term:
    preferred_term: SOX11
    term:
      id: hgnc:11191
      label: SOX11
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  association: >-
    Heterozygous pathogenic variants in SOX11 are the sole established cause of
    this disorder. The MONDO anchor MONDO:0014376 carries a single
    RO:0004003 (has material basis in germline mutation in) relation to
    HGNC:11191 (SOX11).
  notes: >-
    SOX11 (2p25.2) is a single-exon gene encoding a 441-amino-acid SoxC-group
    transcription factor. Pathogenic variation comprises de novo missense
    variants clustering in the HMG DNA-binding domain, truncating (nonsense and
    frameshift) variants, in-frame deletions, and whole-gene 2p25.2
    microdeletions. Because SOX11 is single-exon, truncating transcripts may
    escape nonsense-mediated decay, but the predicted proteins lack or disrupt
    the HMG domain and cannot bind DNA.

    SOX11 is genomically and functionally adjacent to two entities that must not
    be conflated with it: SOX4 (the closest SoxC paralogue, itself a
    Coffin-Siris-spectrum gene) and SOX2 (anophthalmia syndrome). Every citation
    in this entry was checked to confirm the reported gene is SOX11.
  evidence:
  - reference: PMID:24886874
    reference_title: "De novo SOX11 mutations cause Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we apply whole-exome sequencing (WES) to 92 CSS patients, and identify two de novo SOX11 mutations in two unrelated patients."
    explanation: >-
      Original gene-disease assertion for SOX11 based on trio whole-exome
      sequencing.
  - reference: PMID:42168980
    reference_title: "A de novo SOX11 mutation causing hypogonadotropic hypogonadism: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thirty unique variants were identified, 17/30 clustering within the HMG domain and 15/18 proven de-novo."
    explanation: >-
      Summarises the variant spectrum across the published SOX11 literature.
  - reference: PMID:26543203
    reference_title: "Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SOX11 is a single exon gene. Nonsense-mediated decay (NMD) may not occur with mutations in the final exon of a gene"
    explanation: >-
      Explains the single-exon architecture and its implication for the fate of
      truncating transcripts.
diagnosis:
- name: Molecular genetic testing for a heterozygous SOX11 variant
  description: >-
    SOX11-related neurodevelopmental disorder is a genotype-first diagnosis.
    There is no biochemical marker and the facial gestalt is explicitly
    non-specific, so identification of a heterozygous pathogenic SOX11 variant
    by multigene panel or exome/genome sequencing is the confirmatory test.
    SOX11 is one of the genes in which a pathogenic variant establishes the
    Coffin-Siris syndrome diagnosis per GeneReviews, although the SOX11 entity
    is now recognised as clinically and epigenetically distinct from the
    BAF core-subunit BAFopathies (see differential_diagnoses).
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:23556151
    reference_title: "Coffin-Siris Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The diagnosis of CSS is established in a proband with suggestive findings and a heterozygous pathogenic variant in one of the following 14 known genes identified by molecular genetic testing: ARID1A, ARID1B, ARID2, BICRA, DPF2, PHF6, SMARCA2, SMARCA4, SMARCB1, SMARCC2, SMARCD1, SMARCE1, SOX4, or SOX11."
    explanation: >-
      GeneReviews Diagnosis/Testing section, naming SOX11 explicitly among the
      genes in which a heterozygous pathogenic variant establishes the
      diagnosis by molecular genetic testing.
  - reference: PMID:26543203
    reference_title: "Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We used array based comparative genomic hybridisation and trio exome sequencing to identify children with intellectual disability who have deletions or de novo point mutations disrupting SOX11."
    explanation: >-
      Documents the two complementary assays that detect the two lesion classes
      in this disorder: chromosomal microarray for whole-gene 2p25 deletions,
      and trio exome sequencing for de novo intragenic point variants.
  notes: >-
    SOX11 is a single-exon gene, so exome-based CNV callers with poor
    single-exon sensitivity may miss an intragenic deletion; the single-exon
    architecture is evidenced in the genetic section. No frequency of diagnostic
    yield is asserted because no SOX11-specific yield study exists.
- name: Blood DNA methylation episignature testing (EpiSign)
  description: >-
    Genome-wide DNA methylation profiling of peripheral blood identifies a
    SOX11-specific episignature that separates SOX11 syndrome from the BAF
    (SWI/SNF) core-subunit BAFopathies with which it is clinically confused.
    It is used both to confirm the diagnosis and to reclassify variants of
    uncertain significance. This assay is the discriminator the entity boundary
    rests on, and is modelled here as a diagnostic in addition to its
    pathophysiology node.
  diagnosis_term:
    preferred_term: DNA Methylation Analysis
    term:
      id: NCIT:C63328
      label: DNA Methylation Analysis
  evidence:
  - reference: PMID:35341651
    reference_title: "SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Blood DNA methylation was assessed using Infinium MethylationEPIC array."
    explanation: >-
      Names the assay platform: genome-wide methylation array on peripheral
      blood DNA, the specimen and technology used clinically.
  - reference: PMID:35341651
    reference_title: "SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A distinctive pattern of blood DNA methylation was identified in SOX11 syndrome, separating SOX11 syndrome from other BAFopathies."
    explanation: >-
      States the discriminating performance that gives the assay its diagnostic
      value: it separates SOX11 syndrome from the BAFopathies, which is exactly
      the differential this entry's lump/split rationale turns on.
  markers: SOX11-specific peripheral-blood DNA methylation episignature
  notes: >-
    The episignature was derived from a small training set and the published
    per-probe detail (224 differentially methylated probes, methylation variant
    pathogenicity score, 10 cases vs 50 matched controls) sits in the paper's
    body text. Only the abstract of PMID:35341651 is obtainable - a re-fetch on
    2026-07-31 returned content_type abstract_only despite PMCID PMC9245088 -
    so those numbers are deliberately not asserted here rather than quoted from
    an unverifiable source. No sensitivity or specificity figure is asserted for
    the same reason.
treatments:
- name: Multidisciplinary Developmental and Behavioural Support
  description: >-
    Standard management for developmental delay and intellectual disability:
    early intervention, special education, speech and language therapy,
    physiotherapy, occupational therapy, and behavioural assessment and support
    for ADHD, anxiety, aggression, and autistic features. No disease-modifying
    therapy exists.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:23556151
    reference_title: "Coffin-Siris Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Standard treatment for developmental delay / intellectual disability, epilepsy, tics, sleep disturbance, scoliosis, joint laxity, knee subluxations, obesity, refractive error, strabismus, ptosis, hearing loss, congenital heart defects, undervirilization, inguinal hernia, frequent infections, and hepatoblastoma."
    explanation: >-
      GeneReviews management recommendation for the Coffin-Siris syndrome
      spectrum, of which SOX11 is one of the 14 listed genes. Expert-consensus
      guidance rather than trial data, hence evidence_source OTHER.
- name: Feeding Therapy and Nutritional Support
  description: >-
    Feeding therapy for infantile feeding difficulty, with consideration of
    gastrostomy tube placement when feeding problems persist.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: nutritional support
    term:
      id: NCIT:C15433
      label: Nutritional Support
  evidence:
  - reference: PMID:23556151
    reference_title: "Coffin-Siris Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Feeding therapy with consideration of placement of gastrostomy tube in those with persistent feeding issues."
    explanation: >-
      GeneReviews management recommendation matching the feeding difficulty
      documented in SOX11 cohorts.
- name: Pulsatile GnRH Therapy for Hypogonadotropic Hypogonadism
  description: >-
    Pulsatile gonadotropin-releasing hormone (GnRH pump) therapy to induce
    puberty and restore gonadotropin secretion in SOX11-related hypogonadotropic
    hypogonadism. Reported to restore gonadotropin output within 72 hours in a
    single treated proband; this is single-case evidence, not trial evidence.
  therapeutic_modality: PEPTIDE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: gonadorelin
      term:
        id: CHEBI:5520
        label: gonadorelin
  target_mechanisms:
  - target: Impaired Hypothalamic-Pituitary Gonadotropic Axis Development
    treatment_effect: BYPASSES
    description: >-
      Exogenous pulsatile GnRH bypasses the deficient hypothalamic GnRH pulse
      generator and drives pituitary gonadotropin release.
  evidence:
  - reference: PMID:42168980
    reference_title: "A de novo SOX11 mutation causing hypogonadotropic hypogonadism: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GnRH-pump therapy restored gonadotropin output within 72 h."
    explanation: >-
      Single-patient report of biochemical response to pulsatile GnRH in a
      SOX11 variant carrier with Kallmann-criteria hypogonadotropic
      hypogonadism.
- name: Endocrine, Ophthalmological and Audiological Surveillance
  description: >-
    Baseline and periodic endocrine assessment (including pubertal staging and
    anterior pituitary hormone screening), MRI of the olfactory tracts and
    pituitary, annual ophthalmology and audiology evaluation. MRI is
    specifically useful for delineating cochlear nerve deficiency.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:42168980
    reference_title: "A de novo SOX11 mutation causing hypogonadotropic hypogonadism: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mandating comprehensive baseline evaluation-including endocrine assessment, neurodevelopmental screening, and MRI of olfactory tracts and pituitary-regardless of initial presentation"
    explanation: >-
      Explicit surveillance recommendation from the SOX11-related-disorder
      literature review.
  - reference: PMID:35642566
    reference_title: "Cochlear nerve deficiency in SOX11-related Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Magnetic resonance imaging is useful in delineating the cochlear nerve deficiency and other CSS-related brain malformations."
    explanation: >-
      Supports MRI as the modality for detecting the cochlear nerve deficiency
      arm of the phenotype.
  - reference: PMID:23556151
    reference_title: "Coffin-Siris Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Annually or as clinically indicated, ophthalmology evaluation and vision assessment; audiology evaluation."
    explanation: >-
      GeneReviews surveillance schedule for the Coffin-Siris spectrum, directly
      relevant to the ocular and auditory features of the SOX11 entity.
- name: Genetic Counseling
  description: >-
    Autosomal dominant counselling. Most cases are de novo, giving a low but
    non-zero recurrence risk from germline mosaicism; parental testing is
    required because transmission from a mildly affected parent has been
    reported. Prenatal and preimplantation genetic testing are possible once the
    familial variant is known.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:23556151
    reference_title: "Coffin-Siris Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "If the CSS-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible."
    explanation: >-
      GeneReviews genetic counselling guidance for the Coffin-Siris spectrum
      including SOX11.
  - reference: PMID:33785884
    reference_title: "Maternal transmission of a mild Coffin-Siris syndrome phenotype caused by a SOX11 missense variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Maternal transmission of a mild Coffin-Siris syndrome phenotype caused by a SOX11 missense variant."
    explanation: >-
      Justifies parental testing rather than assuming de novo occurrence.
differential_diagnoses:
- name: Coffin-Siris syndrome due to BAF (SWI/SNF) core-subunit variants
  description: >-
    Classical Coffin-Siris syndrome is caused by heterozygous variants in genes
    encoding subunits of the BAF/SWI-SNF chromatin remodelling complex
    (ARID1A, ARID1B, ARID2, DPF2, SMARCA4, SMARCB1, SMARCC2, SMARCD1,
    SMARCE1, BICRA) plus PHF6. SOX11 shares the clinical label
    "Coffin-Siris syndrome 9" but is a transcription factor acting DOWNSTREAM
    of the PAX6-BAF complex, not a component of it. This is the single most
    important named-entity distinction for this entry: BAF core-subunit cohort
    phenotype data must NOT be attributed to SOX11.
  distinguishing_features:
  - Molecular criterion - the causal variant is in SOX11 (2p25.2), not in a BAF subunit gene; SOX11 and BAF-subunit variants are mutually exclusive in Coffin-Siris cohorts.
  - Episignature - blood DNA methylation profiling separates SOX11 syndrome from the BAFopathies.
  - Mechanism - SOX11 is transcriptionally downstream of the PAX6-BAF complex (BRG1/SMARCA4 binds the SOX11 promoter), so SOX11 loss is a narrower lesion than loss of the remodeller itself.
  - Severity - BAF core-subunit disease tends to be more severe; SOX11 accounts for only about 2% of Coffin-Siris cohorts and clusters at the milder dysmorphic end while carrying a heavier microcephaly burden.
  - Epilepsy burden - GeneReviews reports epilepsy in about half of Coffin-Siris syndrome overall, whereas epilepsy is distinctly uncommon in reported SOX11 cohorts. Importing the Coffin-Siris epilepsy frequency into a SOX11 entry would materially misstate the phenotype, so no epilepsy frequency is curated here.
  - Coarse facies - coarse facial features are a hallmark of ARID1B Coffin-Siris syndrome and are characteristically absent in SOX11 disease, making facial gestalt a discriminator in the opposite direction to the historical CSS9 label.
  - Cancer surveillance - the ARID1A-specific AFP/hepatoblastoma surveillance recommendation in the Coffin-Siris GeneReviews chapter is gene-specific and is deliberately NOT applied to SOX11; no cancer predisposition has been reported with germline SOX11 variants.
  - Direction of the SOX11-BAF relationship is not fixed - in germline neurodevelopmental disease SOX11 sits downstream of PAX6-BAF, whereas in adrenergic neuroblastoma SOX11 acts upstream of and regulates SWI/SNF core components including SMARCA4 and ARID1A. The somatic over-expression biology is separate and must not be imported into this germline entry.
  evidence:
  - reference: PMID:35341651
    reference_title: "SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SOX11 syndrome is a distinct clinical entity with characteristic clinical features and episignature differentiating it from BAFopathies."
    explanation: >-
      Primary evidence for keeping SOX11 split from the BAFopathies rather than
      lumping it into classical Coffin-Siris syndrome.
  - reference: PMID:24886874
    reference_title: "De novo SOX11 mutations cause Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SOX11 is the downstream transcriptional factor of the PAX6-BAF complex, highlighting the importance of the BAF complex and SOX11 transcriptional network in brain development."
    explanation: >-
      Establishes the downstream (non-core-subunit) position of SOX11 relative
      to the BAF complex.
  - reference: PMID:24886874
    reference_title: "De novo SOX11 mutations cause Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mutations of SOX11 and other BAF subunit genes are mutually exclusive in CSS."
    explanation: >-
      Mutual exclusivity confirms these are separate molecular causes rather
      than co-occurring lesions.
  - reference: PMID:24886874
    reference_title: "De novo SOX11 mutations cause Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SOX11 mutations appear to be a rare cause of CSS as only 2 out of 92 patients (2.2%) showed SOX11 abnormality and to be limited to the mild end of CSS phenotype."
    explanation: >-
      Quantifies the small SOX11 share of Coffin-Siris cohorts, another reason
      not to import BAF-cohort statistics into this entry.
  - reference: PMID:23556151
    reference_title: "Coffin-Siris Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "About half of affected individuals have epilepsy."
    explanation: >-
      The Coffin-Siris epilepsy figure that must NOT be attributed to SOX11;
      quoted here explicitly so the boundary is auditable rather than implicit.
  - reference: PMID:36882421
    reference_title: "SOX11 regulates SWI/SNF complex components as member of the adrenergic neuroblastoma core regulatory circuitry."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Most notably, SOX11 controls chromatin regulatory complexes, including 10 SWI/SNF core components among which SMARCC1, SMARCA4/BRG1 and ARID1A."
    explanation: >-
      Demonstrates that the SOX11-BAF relationship is bidirectional and
      context-dependent. This is somatic neuroblastoma biology and is cited only
      to justify keeping the germline entry mechanistically separate; it is not
      curated as a mechanism of the neurodevelopmental disorder.
  notes: >-
    MONDO:0014376 is currently modelled as is_a MONDO:0015452 (Coffin-Siris
    syndrome). This entry retains MONDO:0014376 as its anchor but curates the
    SOX11 entity in its own right and does not inherit BAF-subunit cohort data.
    For the same reason disease_term is deliberately left UNBOUND on this
    differential: MONDO:0015452 is this entry's own superclass, so binding it
    would make the entry machine-assert its ancestor as a differential
    diagnosis. The prose here concerns the BAF core-subunit SIBLINGS (ARID1B,
    SMARCB1, SMARCA4, ARID1A), which the grouping term does not isolate, and
    binding a single subtype such as MONDO:0007617 would narrow the
    differential to one gene and misstate it in the other direction.
- name: SOX4-related neurodevelopmental disorder (Coffin-Siris syndrome 10)
  disease_term:
    preferred_term: Coffin-Siris syndrome 10
    term:
      id: MONDO:0032791
      label: Coffin-Siris syndrome 10
  description: >-
    SOX4 is the closest SoxC paralogue of SOX11 and is also listed as a
    Coffin-Siris syndrome gene in GeneReviews. The phenotypes overlap
    substantially, so gene identity - not clinical gestalt - is the
    discriminator.
  distinguishing_features:
  - The causal variant is in SOX4, not SOX11; the two are separate MONDO/OMIM entities despite overlapping presentations.
  - SOX11-specific findings such as the SOX11 blood methylation episignature and the documented hypogonadotropic hypogonadism association are not established for SOX4.
  evidence:
  - reference: PMID:23556151
    reference_title: "Coffin-Siris Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ARID1B, ARID2, BICRA, DPF2, PHF6, SMARCA2, SMARCA4, SMARCB1, SMARCC2, SMARCD1, SMARCE1, SOX4, or SOX11."
    explanation: >-
      GeneReviews lists SOX4 and SOX11 as separate Coffin-Siris-spectrum genes,
      confirming they are distinct entities that share a clinical label.
- name: SOX2-related anophthalmia syndrome
  notes: >-
    disease_term left unbound, but NOT because no term exists - an earlier
    version of this rationale said so and was wrong. MONDO:0008799
    (OMIM:206900) carries "SOX2 anophthalmia syndrome" as a RELATED synonym and
    is the canonical SOX2 disorder. It is not bound here because its primary
    label, "anophthalmia/microphthalmia-esophageal atresia syndrome",
    foregrounds a feature (oesophageal atresia) that is not what makes SOX2 a
    differential for this entry; binding it would overstate the resemblance.
    Recorded explicitly so the next curator is not told to stop looking for a
    term that does exist.
  description: >-
    SOX2 haploinsufficiency causes anophthalmia/microphthalmia with
    developmental delay. Because SOX11 loss can also produce microphthalmia and
    developmental delay, SOX2 is a realistic clinical and named-entity
    confusion, but SOX2 belongs to the SoxB1 group and is a different gene at a
    different locus.
  distinguishing_features:
  - Severe bilateral anophthalmia is characteristic of SOX2 and is not a feature of SOX11-related disorder, in which ocular malformation is infrequent and usually milder.
  - Fifth-digit nail/phalanx hypoplasia, hypogonadotropic hypogonadism with olfactory bulb hypoplasia, and the SOX11 episignature point to SOX11.
  evidence:
  - reference: PMID:24886874
    reference_title: "De novo SOX11 mutations cause Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "of other SOX genes ( SOX2, SOX9 and SOX10) is known to cause human diseases"
    explanation: >-
      Confirms SOX2 as a separate SOX-family disease gene, distinguishing it
      from SOX11.
- name: Pitt-Hopkins syndrome (TCF4)
  disease_term:
    preferred_term: Pitt-Hopkins syndrome
    term:
      id: MONDO:0012589
      label: Pitt-Hopkins syndrome
  description: >-
    A subset of individuals with SOX11 variants present with a clinical gestalt
    indistinguishable from Pitt-Hopkins syndrome, so a negative TCF4 result in a
    clinically diagnosed Pitt-Hopkins patient should prompt SOX11 testing.
  distinguishing_features:
  - Pitt-Hopkins syndrome is caused by TCF4 haploinsufficiency; a normal TCF4 result with a clinical Pitt-Hopkins gestalt should trigger broader sequencing.
  - Approximately 22% of well-characterised published SOX11 cases have a Pitt-Hopkins-overlapping presentation.
  evidence:
  - reference: PMID:37558216
    reference_title: "Pathogenic variants in SOX11 mimicking Pitt-Hopkins syndrome phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By reviewing both clinically and genetically 32 out of 82 subjects reported in the literature with SOX11 variants, for whom detailed information are provided, we found that 7/32 (22%) had a clinical presentation overlapping PTHS."
    explanation: >-
      Quantifies the Pitt-Hopkins overlap and establishes SOX11 as a
      differential for TCF4-negative Pitt-Hopkins.
- name: Contiguous-gene 2p25 deletion phenotypes (MYCN, MYT1L)
  description: >-
    Larger 2p25 deletions that remove SOX11 can also remove MYCN (Feingold
    syndrome) or MYT1L, so the phenotype of a deletion carrier may not be
    attributable to SOX11 alone.
  distinguishing_features:
  - Deletion breakpoint mapping determines which additional genes are lost; deletions containing SOX11 alone isolate the SOX11 contribution.
  - MYT1L-only deletions tend to cause macrocephaly, whereas SOX11-containing deletions cause microcephaly.
  evidence:
  - reference: PMID:26543203
    reference_title: "Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Several other genes within the deleted 2p25 regions could contribute to the observed phenotypes."
    explanation: >-
      Explicit caution against attributing all deletion-carrier features to
      SOX11 haploinsufficiency.
  - reference: PMID:26543203
    reference_title: "Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This suggests that SOX11 haploinsufficiency may exert a powerful, negative influence on brain growth."
    explanation: >-
      The opposite head-size direction of MYT1L-only versus SOX11-containing
      deletions is what isolates the SOX11 contribution to microcephaly.
discussions:
- discussion_id: sox11_phenotype_frequency_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What is the true population frequency of each SOX11 phenotype, and in
    particular of hypogonadotropic hypogonadism and ocular malformation?
  attaches_to:
  - pathophysiology#Impaired Hypothalamic-Pituitary Gonadotropic Axis Development
  - pathophysiology#Disrupted Ocular Morphogenesis
  rationale: >-
    The two qualifying features in the OMIM/MONDO disease name are ocular
    malformation and hypogonadotropic hypogonadism, both described as optional.
    The ocular half of that gap is now partly closed: a 2025 systematic
    ophthalmological review (PMID:40933692) pools 58 published single-nucleotide
    variant cases and reports ophthalmological malformation in 26/58 (44.83%),
    with ocular motor disorder the most prevalent subtype at 15/58 (29.31%).
    That pooled figure is what the Ophthalmological Malformation phenotype is
    banded on. It does not resolve the apraxia-specific rate, because "ocular
    motor disorder" is a broader category than Cogan-type oculomotor apraxia,
    and it does not address hypogonadotropic hypogonadism, for which no
    denominator-based frequency has been published in a source obtainable here.
    Elsewhere in the entry, bands are now derived preferentially from the pooled
    literature table in PMID:35938035 (Table 1, "Phenotypic comparison of our
    patient with reported patients", n = 58 reported patients) rather than from
    the 7-patient Sanchez-Martin series: intellectual disability 38/40 (95%,
    VERY_FREQUENT, upgraded from FREQUENT), developmental delay 36/37 (97%),
    microcephaly 11/28 (39%), short stature 10/30 (33%), fifth-finger
    clinodactyly 10/55 (18%, OCCASIONAL - corrected down from FREQUENT, which
    had been derived from the n=7 outlier figure of 5/7), and hypoplastic nails
    6/55 (11%, OCCASIONAL - previously unbanded). Each pooled row has a
    phenotype-specific denominator smaller than 58 because the row reflects only
    those individuals in whom the feature was reported; cryptorchidism 5/6 is
    left unbanded for that reason, since 6 is the reporting-conditional subset
    of 28 reported males. Two denominators remain out of reach: the 38-patient
    Al-Jawahiri cohort (PMID:35341651) reports per-phenotype counts only in body
    text, and a re-fetch on 2026-07-31 still returned an abstract-only cache
    despite the paper carrying PMCID PMC9245088, so its hypogonadotropic
    hypogonadism (8/38) and abnormal brain MRI (12/20) figures are not asserted
    here. Bands continue to be omitted rather than guessed wherever no
    denominator is quotable from a cached source.
  proposed_experiments:
  - experiment_id: sox11_denominator_phenotyping
    name: Denominator-based multisystem phenotyping of the full SOX11 cohort
    description: >-
      Systematic phenotyping of the full published and registry SOX11 cohort
      with mandatory endocrine and ophthalmological evaluation of every
      participant, so that the "with or without" qualifiers in the disease name
      can be replaced with real frequencies rather than ascertainment-biased
      case counts.
    decision_criterion: >-
      Per-phenotype frequencies with explicit denominators for hypogonadotropic
      hypogonadism and ocular malformation across an unselected SOX11 cohort.
- discussion_id: sox11_dosage_model_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Do the homozygous-null and morpholino knockdown models used for SOX11
    faithfully represent the human heterozygous loss-of-function state?
  attaches_to:
  - pathophysiology#Reduced Cortical Neurogenesis and Brain Growth
  - pathophysiology#Impaired Cochlear Nerve Development
  - pathophysiology#Disrupted Nephrogenic Gdnf Domain Restriction
  - pathophysiology#Mandibular Hypoplasia with Secondary Palatal Shelf Obstruction
  rationale: >-
    Much of the mechanistic evidence for the microcephaly and cochlear-nerve
    arms comes from homozygous Sox11-null mice, zebrafish sox11a/b double
    morphants, and Xenopus morphants - all effectively complete loss of
    function - whereas human disease is heterozygous. Tsurusaki et al. note that
    physical and functional abnormalities in heterozygous mice have not been
    described. The dosage mismatch is partly mitigated by the isogenic
    SOX11+/- human embryonic stem cell model (PMID:31035284), which is the
    strongest dosage-matched evidence available, but that model is in vitro.
    The same zygosity caveat applies to the organ arms added from the deep
    research: the duplex-kidney and secondary-cleft-palate mechanisms come from
    Sox11 whole-gene-deletion mice, and the corresponding human findings in
    heterozygotes are milder (small or malrotated kidney; cleft palate in a
    single reported individual). The C. elegans model is explicit that the
    orthologous Y116C change is recessive, which is itself a dosage mismatch
    with the dominant human disease even though it supports the loss-of-function
    interpretation.
  evidence:
  - reference: PMID:24886874
    reference_title: "De novo SOX11 mutations cause Coffin-Siris syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Physical and functional abnormalities in hetero- zygotes have not been described."
    explanation: >-
      States directly that the heterozygous mouse - the dosage-matched model -
      has not been characterised, which is the substance of the mismatch.
  proposed_experiments:
  - experiment_id: sox11_het_mouse_deep_phenotyping
    name: Deep phenotyping of Sox11 heterozygous mice
    description: >-
      Characterise head size, cortical neuron number, and auditory brainstem
      response in Sox11 heterozygous mice, the dosage-matched in vivo model that
      has not previously been assessed.
    decision_criterion: >-
      Reduced brain size, reduced cortical neuron number, or elevated ABR
      thresholds in heterozygotes relative to littermate controls would confirm
      that single-copy loss is sufficient in vivo.
  - experiment_id: sox11_het_organoid
    name: Isogenic SOX11+/- human cerebral organoids
    description: >-
      Extend the existing two-dimensional isogenic SOX11+/- human embryonic stem
      cell model to three-dimensional cerebral organoids to test whether
      heterozygous dosage alone reduces neuron output in a human cortical
      context that includes outer radial glia.
    decision_criterion: >-
      Reduced organoid size and cortical neuron output in SOX11+/- versus
      isogenic wild-type organoids.
- discussion_id: sox11_noncoding_and_natural_history_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What is the adult natural history of SOX11-related neurodevelopmental
    disorder, and do non-coding regulatory variants at the SOX11 locus cause it?
  attaches_to:
  - pathophysiology#Heterozygous SOX11 Loss of Function
  rationale: >-
    Two distinct gaps sit on the same node. First, every reported pathogenic
    lesion to date is coding or whole-gene: no non-coding or regulatory SOX11
    variant has been reported, despite a documented enhancer landscape at the
    locus, so the mutational spectrum in this entry may be incomplete by
    ascertainment rather than by biology. Second, the published cohort is
    paediatric-dominated; there is no natural-history study, no disease-specific
    quality-of-life instrument, no prognostic biomarker, and no clinical trial
    for this disorder, so the progression and outcome sections of this entry are
    intentionally empty rather than inferred.
  proposed_experiments:
  - experiment_id: sox11_regulatory_region_sequencing
    name: Targeted regulatory-region sequencing at the SOX11 locus
    description: >-
      Sequence the SOX11 promoter and annotated enhancer landscape in
      coding-negative individuals with a SOX11-syndrome-like phenotype or a
      SOX11 episignature, to test whether non-coding lesions account for
      unexplained cases.
    decision_criterion: >-
      Identification of a non-coding variant that segregates with phenotype and
      reduces SOX11 expression in a reporter assay.
  - experiment_id: sox11_adult_natural_history
    name: Prospective adult natural-history study
    description: >-
      Longitudinal follow-up of a molecularly confirmed SOX11 cohort into
      adulthood with standardised endocrine, ophthalmological, audiological,
      skeletal, and adaptive-function outcome measures.
    decision_criterion: >-
      Age-stratified outcome data sufficient to populate progression and
      prognosis for the entry.
references:
- reference: PMID:23556151
  title: "Coffin-Siris Syndrome."
  tags:
  - GeneReviews
- reference: PMID:24886874
  title: "De novo SOX11 mutations cause Coffin-Siris syndrome."
- reference: PMID:25010521
  title: "Sox11 is required to maintain proper levels of Hedgehog signaling during vertebrate ocular morphogenesis."
- reference: PMID:26543203
  title: "Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome."
- reference: PMID:26826126
  title: "Ablation of the Sox11 Gene Results in Clefting of the Secondary Palate Resembling the Pierre Robin Sequence."
- reference: PMID:28787104
  title: "Coffin-Siris syndrome and cardiac anomaly with a novel SOX11 mutation."
- reference: PMID:29437512
  title: "Observation of Cleft Palate in an Individual with SOX11 Mutation: Indication of a Role for SOX11 in Human Palatogenesis."
- reference: PMID:29459093
  title: "Sox11 gene disruption causes congenital anomalies of the kidney and urinary tract (CAKUT)."
- reference: PMID:31035284
  title: "A novel human stem cell model for Coffin-Siris syndrome-like syndrome reveals the importance of SOX11 dosage for neuronal differentiation and survival."
- reference: PMID:32574812
  title: "Regulatory roles for SOX11 in development, stem cells and cancer."
- reference: PMID:33579706
  title: "Usp11 controls cortical neurogenesis and neuronal migration through Sox11 stabilization."
- reference: PMID:33785884
  title: "Maternal transmission of a mild Coffin-Siris syndrome phenotype caused by a SOX11 missense variant."
- reference: PMID:35341651
  title: "SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile."
- reference: PMID:35642566
  title: "Cochlear nerve deficiency in SOX11-related Coffin-Siris syndrome."
- reference: PMID:35938035
  title: "Identification and functional analysis of novel SOX11 variants in Chinese patients with Coffin-Siris syndrome 9."
- reference: PMID:36369738
  title: "Two SOX11 variants cause Coffin-Siris syndrome with a new feature of sensorineural hearing loss."
- reference: PMID:36882421
  title: "SOX11 regulates SWI/SNF complex components as member of the adrenergic neuroblastoma core regulatory circuitry."
- reference: PMID:37558216
  title: "Pathogenic variants in SOX11 mimicking Pitt-Hopkins syndrome phenotype."
- reference: PMID:37924570
  title: "Short report: Behavioural characterisation of SOX11 syndrome."
- reference: PMID:39290158
  title: "Expanding the Spectrum of Endocrine Abnormalities Associated With SOX11-related Disorders."
- reference: PMID:39333428
  title: "Novel variants in the SOX11 gene: clinical description of seven new patients."
- reference: PMID:40832700
  title: "A Coffin-Siris syndrome-associated mutation modeled in Caenorhabditis elegans affects multiple developmental processes."
- reference: PMID:40933692
  title: "Case Report: Observation of early-onset high myopia with fundus tessellation changes in Coffin-Siris syndrome 9 (CSS9) and literature review."
- reference: PMID:42168980
  title: "A de novo SOX11 mutation causing hypogonadotropic hypogonadism: a case report and literature review."
notes: >-
  GeneReviews baseline. There is no SOX11-specific GeneReviews chapter; the
  Coffin-Siris Syndrome chapter (PMID:23556151) is the applicable expert-curated
  reference and lists SOX11 as one of 14 Coffin-Siris-spectrum genes. Its
  Clinical Characteristics section aggregates all 14 genes and is therefore
  dominated by BAF core-subunit cases, so it is used here for the gene list,
  management, surveillance, and genetic counselling, and is NOT used as the
  source of SOX11 phenotype frequencies.


  Lump-versus-split decision. This entry is curated as a distinct disease rather
  than as a presentation of classical Coffin-Siris syndrome, on three grounds:
  (1) mechanism - SOX11 is a transcription factor acting downstream of the
  PAX6-BAF complex, not a BAF core subunit, and SOX11 and BAF-subunit variants
  are mutually exclusive in Coffin-Siris cohorts (PMID:24886874); (2) molecular
  class separation - SOX11 cases carry a blood DNA methylation episignature that
  separates them from the BAFopathies (PMID:35341651); (3) phenotype -
  SOX11 disease carries a distinctive burden of microcephaly, hypogonadotropic
  hypogonadism, and infrequent congenital malformations relative to classical
  Coffin-Siris syndrome (PMID:37558216, PMID:35341651). MONDO currently places
  MONDO:0014376 as is_a MONDO:0015452 (Coffin-Siris syndrome); that placement is
  retained as the ontology anchor without importing BAF cohort data.


  Frequency-band provenance. Phenotype bands are derived preferentially from the
  pooled literature table in PMID:35938035 (Table 1, n = 58 reported patients)
  and, for the ocular arm, from the pooled 58-case ophthalmological review
  PMID:40933692, in preference to the 7-patient series PMID:39333428. The
  derivation for each band is shown in the corresponding evidence explanation
  and summarised in the sox11_phenotype_frequency_gap discussion.


  Claims deliberately not curated for want of a quotable source. The
  Al-Jawahiri cohort (PMID:35341651) reports its per-phenotype denominators only
  in body text; the cache is content_type abstract_only and a re-fetch on
  2026-07-31 did not obtain full text despite PMCID PMC9245088. Consequently the
  following are NOT asserted anywhere in this entry: hypogonadotropic
  hypogonadism 8/38, developmental delay / intellectual disability 37/38,
  abnormal brain MRI 12/20, agenesis of the corpus callosum, anterior pituitary
  hypoplasia, and the episignature's 224-probe / 10-case-vs-50-control training
  detail. Cerebellar vermis hypoplasia IS curated, unbanded, because a single
  case with an isolated de novo SOX11 nonsense variant and a normal array CGH is
  quotable from the full text of PMID:26543203.


  Impaired Adaptive Behaviour carries no ontology term. The construct measured is
  a Vineland adaptive-behaviour composite; HP:0006889 (Borderline intellectual
  disability) was used as a proxy in the initial version of this entry and has
  been removed, since it names a cognitive band rather than adaptive function
  and would misrepresent the finding. A new HPO term request for an
  adaptive-behaviour impairment concept is the correct resolution.

  GeneReviews cross-check. The Coffin-Siris Syndrome GeneReviews Clinical
  Characteristics items were checked one by one against this entry. Captured
  here with SOX11-specific citations: developmental delay/intellectual
  disability, feeding difficulties, hypotonia, hearing impairment, eye issues,
  congenital heart defects, behavioural issues, and fifth-digit nail/phalanx
  hypoplasia. Deliberately NOT imported because no SOX11-specific source was
  found for them: epilepsy ("about half of affected individuals"), frequent
  infections, joint laxity, scoliosis, ptosis, strabismus, obesity, tics, sleep
  disturbance, genitourinary malformations, and the ARID1A-specific
  hepatoblastoma surveillance. Those figures come from BAF-core-subunit-dominated
  cohorts and importing them would be exactly the named-entity error this entry
  is written to avoid. The GeneReviews "Agents/Circumstances to Avoid" section
  contains no drug-safety warning in the cached abstract, so no treatment carries
  one.

  MONDO anchoring. The deep-research report recommended MONDO:0100626
  ("SOX11-related complex neurodevelopmental disorder with or without congenital
  anomalies", the ClinGen-grounded term) as the disease_term in preference to
  MONDO:0014376. Both terms carry the same RO:0004003 relation to HGNC:11191
  (SOX11), and MONDO lists this entry's anchor label as a NARROW synonym of
  MONDO:0100626. This entry keeps MONDO:0014376 because that is the term the
  curation request and the tracking issue specify, and records MONDO:0100626
  under mappings as a skos:broadMatch so a future re-anchoring is a one-line
  change. This is a deliberate, documented deviation from the report.

  Deep research provenance. One provider was run: claude_code (23 minutes, 8 web
  searches, 53 citations). Its recommendations were treated as leads. Every PMID
  it surfaced that is cited here was fetched with just fetch-reference and every
  snippet was verified as a byte-exact substring of the cached abstract. Content
  the report marked [FULL-TEXT] (body text of the open-access Al-Jawahiri 2022
  paper) was NOT used for snippets, because body text does not validate against
  a PubMed-abstract cache; where those figures were valuable but unquotable
  (per-phenotype denominators from the 38-patient cohort, cerebellar hypoplasia,
  corpus callosum agenesis, pituitary hypoplasia, the 224-probe episignature
  detail, the ~21% hypogonadotropic hypogonadism rate) the claim was either
  dropped or carried in prose without a frequency band. The report also flagged
  an HPO typo in its primary source (HP:0013272 for abnormal eye morphology,
  which should be HP:0012372); neither ID is used here.

  Evidence limitations. No population prevalence estimate was found for this
  disorder and none is asserted. Frequency bands are given only where a
  denominator exists in a cited abstract, and the largest such denominator is
  small (n=7 for the clinical-feature counts, n=21 for the behavioural
  measures); the 38-patient Al-Jawahiri cohort abstract reports the
  episignature and the hypogonadotropic hypogonadism association but no
  per-phenotype denominators, so its numbers could not be used. Cleft palate,
  coarctation of the aorta, cochlear nerve hypoplasia, and olfactory bulb
  hypoplasia rest on single case reports and carry no frequency.

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